THE  UNIVERSITY 
OF  ILLINOIS 
LIBRARY 


Return  this  book  on  or  before  the 
Latest  Date  stamped  below. 

University  of  Illinois  Library 

L161— H41 

THERAPEUTIC  IMMUNISATION 


By  the  same  Author, 


PULMONARY  TUBERCULOSIS 

Its  Diagnosis,  Prevention 
and  Treatment. 


Coloured  Frontispiece  and  20  Illustrations, 
Price  6s.  net. 


THERAPEUTIC  IMMUNISATION 

THEORY  AND  PRACTICE 


BY 

W.  M   CROFTON,  M.D. 

Lecturer  in  Special  Pathology,  University  College,  Dublin  ; 
Visiting  Physician,   Royal  National  Hospital  for 
Consumption  in  Ireland  ;  Pathologist  to  Dr. 
Steevens*  Hospital ;  late  Temp.  Capt., 
R.A.M.C. 


PHILADELPHIA 

P.  BLAKISTON'S  SON  &  CO. 

1012  WALNUT  STREET 
1918 


Prmted  in  Great  Britain 


K 


PREFACE. 


This  book  contains  the  substance  of  the  lectures  I 
have  delivered  annually  for  the  last  seven  years  at 
University  College. 

There  seems  to  be  a  general  feeling  in  the  pro- 
fession that  vaccine  therapy  is  a  comparative  failure. 
The  feeling  is,  I  think,  justified,  and  the  failure,  in 


^   my  opinion,  is  due  to  the  fact  that  the  usual  practice 
»   is  founded  on  an  incomplete  theory.    I  have  tried  to 
describe  a  more  complete  theory  and  the  practice  I 
have  founded  on  it,  a  practice  that  has  given  and  is 
3^  giving  me  highly  satisfactory  results. 


W.  M.  C. 


University  College, 
Dublin. 


CONTENTS. 

CHAP.  PAGE 

I.    Introduction   i 

II.    Toxins  and  Antitoxins   12 

III.  Bacteriolysis  and  Phagocytosis    ...  29 

IV.  Agglutination,  Precipitation,  Reactions     .  42 
V.    Therapeutic  Immunisation       ....  54 

VI.    Alimentary  Canal   71 

VII.    Respiratory  System   103 

VIII.    Urino-genital  System      .....  125 

IX.    Bones,  Joints,  Wounds     .      .       •       .       .  146 

X.    The  Skin   163 

XI.    Vascular  System,  Lymphatic  System,  Ner- 
vous System,  Eye  and  Ear  ....  173 

XII.    Infections  Produced  by  Streptothrices      .  207 

Index   221 


Therapeutic  Immunisation 
Theory  and  Practice. 

CHAPTER  1. 

INTRODUCTION. 

Immunity,  in  the  sense  in  which  it  is  used  by 
bacteriologists,  is  the  term  applied  to  a  condition  of 
an  animal,  such  that  its  tissues  cannot  be  invaded  by 
a  given  microbe,  or  if  they  are  invaded  the  microbe 
is  certainly  destroyed  by  them.  In  other  words, 
the  tissues  of  the  immune  animal  cannot  be  broken 
down  by  the  microbe  to  form  suitable  food  for 
itself. 

Our  knowledge  of  the  mechanism  which  pro- 
duces this  desirable  state  is  as  yet  far  from  perfect, 
but  it  is  gradually  advancing,  and  the  application  of 
this  knowledge  to  the  immunisation  of  the  patient 
for  prophylaxis  and  treatment  has  instituted  a  new 
era  in  medicine. 

I  shall  not  try  to  give  a  comprehensive  account 
of  the  theories  of  immunity,  but  shall  only  set  forth 
as  much  as  I  hope  will  prove  sufficient  for  the 
successful  appligation  of  theory  to  practice. 


Therapeutic  Immunisation. 

Some  general  considerations  concerning  the  posi- 
tion of  microbes  in  the  economy  of  living  things  is 
first  of  all  necessary. 

Microbes  are  classified  as  a  subdivision  of  the 
fungi  and  are  known  as  '  fission '  fungi  or  Schizo- 
mycetes.  They  are  minute  unicellular  masses  of 
protoplasm,  sometimes  without  a  cell  wall,  some- 
times with  a  cell  wall  of  more  or  less  modified 
protoplasm.  They  have  great  facility  in  adapting 
themselves  to  changes  of  environment  and  display 
remarkable  powers  of  self-preservation  when  cir- 
cumstances are  unfavourable  and  of  reproduction 
when  they  are  favourable. 

For  our  present  purpose  the  Schizomycetes  may 
be  classified  into  three  groups,  according  to  their 
mode  of  life. 

I.  Saprophytes  ;  2.  Symbiotics  ;  3.  Parasites. 

I.  Were  it  not  for  saprophytic  microbes  the 
supply  of  inorganic  nitrogen  in  the  soil  would 
rapidly  become  exhausted.  These  nitrifying 
organisms,  as  they  are  called,  by  means  of  their 
ferments  split  up  dead  organic  material  into  its 
elements.  Treating  the  soil  with  farmyard  manure 
would  be  useless  if  these  organisms  did  not  accom- 
plish this  ;  for  plants  can  only  absorb  their  nitrogen 
as  simple  salts,  which  they  re-elaborate  into  the 
large  organic  molecules,  in  which  form  only  nitrogen 
can  be  metabolised  by  animals. 

These  nitrifying  organisms  are  made  use  of  by 
civilised  communities  for  the  purposes  of  sewage 
disposal.  The  sewage  is  exposed  to  the  action  of 
the  microbes  in  special  receptacles  called  septic 

2 


Introduction. 


tanks,  the  clear,  inodorous  and  innocuous  effluent 
from  which  can  safely  be  run  into  rivers. 

2.  Well-known  examples  of  symbiotic  microbes 
are  those  occurring  in  combination  with  algae  to 
form  lichens  and  in  the  tubercles  on  the  roots  of 
certain  leguminous  plants.  This  latter  combination 
furnishes  another  way  in  which  nitrogen  can  be 
fixed  in  the  soil,  for  it  has  the  power  of  combining 
the  atmospheric  N  with  O  and  H  to  form  simple 
salts.  Large  tracts  of  land  have  been  rendered 
fertile  by  growing  leguminous  crops  infected  with 
these  bacilli. 

Micro-organisms  in  the  intestinal  canal  of  man 
and  other  animals  play  a  part  in  digestion — for 
instance,  a  very  important  part  in  the  digestion  of 
cellulose.  It  has  been  said,  too,  on  a  certain  amount 
of  experimental  evidence,  that  young  animals 
which  have  been  kept  sterile  from  birth  do  not 
thrive  so  well  as  those  which  have  become  normally 
invaded  by  micro-organisms.  There  are  also  certain 
micro-organisms  which  keep  the  human  vagina 
sterile  by  producing  lactic  acid  ;  pathogenic  organ- 
isms can,  as  a  rule,  only  live  in  an  alkaline  medium, 
and  so  such  organisms  introduced  into  the  healthy 
vagina  rapidly  die  out.  Milk  soured  by  microbes, 
which  produce  lactic  acid,  is  extensively  used  at  the 
present  day  to  disinfect  the  large  intestine  of  man  ; 
with  excellent  effect  in  many  cases. 

3.  The  parasitic  micro-organisms  are  those  which 
most  concern  us.  They  differ  from  the  others,  in 
that  they  have  acquired  the  power  of  subsisting  at 
the  expense  of  living  tissues,  first  breaking  them 


Therapeutic  Immunisation. 


down  by  means  of  certain  ferment-like  substances 
which  we,  speaking  from  the  point  of  view  of  the 
attacked,  call  toxins.  These  microbes  we  speak  of 
as  '  pathogenic  '  or  disease-producing. 

There  are  numerous  kinds  of  pathogenic  microbes 
and,  like  the  races  of  other  divisions  of  living  things, 
different  races  have  adapted  themselves  to  different 
conditions  of  environment ;  so  that  one  kind  of 
microbe  is  able  to  live  best  on  one  tissue,  another  on 
another  tissue,  or  one  species  of  microbe  on  some 
one  particular  animal  or  vegetable  and  not  on 
others. 

It  is  therefore  obvious  that  life  could  not  continue 
if  living  protoplasm  had  not  the  power  of  resisting 
this  splitting-up-into-elements  faculty  of  microbes. 
The  war  continuously  waged  between  nitrifying 
organisms  and  the  amoeba  which  inhabit  the  soil 
furnishes  an  illustration  of  the  '  balance '  which  is 
so  nicely  adjusted  between  the  toxin  of  microbes 
and  the  immunity  of  protoplasm.  The  amoeba  lives 
on  the  microbes,  that  is  to  say,  they  are  ingested  and 
digested  by  it.  On  the  other  hand,  when  the  amoeba 
dies  it  is  split  up  by  the  microbes.  We  can  imagine 
that  when  an  amoeba  is  young  and  vigorous  it  can 
ingest  and  digest  large  numbers  of  the  microbes  ; 
but  that  when  it  is  getting  old  it  will  be  able  to 
take  up  fewer  and  fewer  of  them  until  a  time  will 
come  when  the  immunity  of  its  protoplasm  will  be 
so  reduced  that  it  can  no  longer  resist  their  lytic 
powers.  No  doubt  there  are  also  other  physical 
factors  which  would  lower  the  immunity  of  the 
amoeba,  with  the  inevitable  consequence. 

4 


Introduction. 


This  struggle  helps  us,  I  think,  to  realise  how 
much  our  existence  and  health  depend  on  the  pre- 
servation of  the  balance  of  power.  It  is  thought  by 
some  that  pathogenic  microbes  may  serve  a  useful 
purpose  by  killing  off  the  feeble  members  of  the 
community ;  unfortunately  it  is  often  the  most 
useful  members  that  are  destroyed,  having  perhaps 
been  attacked  during  a  temporary  lowering  of  their 
resistance  or  by  an  exceptionally  virulent  strain  of 
microbes. 

It  is  clear,  too,  that  a  pathogenic  microbe  must  be 
immune  to  the  protecting  mechanism  of  the  indivi- 
dual which  it  is  attacking  ;  and  in  certain  cases  it  is 
quite  easy  to  observe  and  to  effect  the  increase  or 
decrease  of  the  immunity,  or,  speaking  from  the  point 
of  view  of  the  attacked,  toxicity  of  a  particular  strain 
of  microbe.  Take,  for  instance,  the  case  of  a  typhoid 
bacillus.  When  first  isolated  from  a  patient  suffering 
from  typhoid  fever  it  may  be  very  virulent  and 
strongly  resistant  to  agglutination  ;  but,  when  kept 
alive  by  transference  from  one  culture  tube  to 
another,  it  gradually  loses  a  large  amount  of  its 
toxicity  and  becomes  easily  agglutinated :  it  has 
no  longer  to  kill  its  food,  and  therefore  the  special 
weapons  for  this  purpose  are  not  developed ;  indeed, 
the  special  stimulants,  viz.,  the  antibodies  of  the 
host  which  caused  the  increased  production  of  toxins 
are  no  longer  present.  On  the  other  hand,  the 
toxicity  of  a  given  strain  of  microbes  can  be  enor- 
mously increased  by  passing  them  through  a  series 
of  susceptible  animals.  In  each  animal  the  microbes 
are  attacked  by  the  antibodies  of  the  host,  which 

5 


Therapeutic  Immunisation. 


are  not  strong  enough  to  kill  or  permanently  injure 
them ;  but  after  a  temporary  lowering  of  the 
toxin-producing  powers  of  the  microbes  their  proto- 
plasm responds  by  producing  more  toxin  than  at 
first.  In  each  animal  the  microbes  receive  an 
additional  stimulus  until  their  toxicity  is  enor- 
mously increased,  it  may  be  to  such  an  extent  that 
whereas  a  huge  number  of  microbes  had  to  be  given 
to  kill  the  first  animal,  the  injection  of  a  single 
microbe  will  prove  fatal  to  the  last.  This  decrease 
and  subsequent  increase  in  virulence  is  probably 
one  factor  in  the  incubation  period  after  infection. 
The  same  phenomenon  also  serves  to  illustrate  how 
a  susceptible  person — for  instance,  an  individual 
unvaccinated  against  small-pox — may  be  a  danger 
to  the  community,  for  if  he  is  attacked  by  the 
disease  he  may  pass  on  a  much  more  powerful  virus 
to  the  people  he  infects. 

No  hard-and-fast  line  can  be  drawn  between  the 
saprophytic  and  the  pathogenic  microbes,  for  some 
microbes  which  have  been  leading  a  saprophytic 
existence  can  become  pathogenic  if  the  balance  is 
upset  in  their  favour.  '  Carriers '  of  infectious 
disease  well  illustrate  this  point.  During  an  epi- 
demic of  diphtheria,  for  instance,  many  people, 
who  are  quite  well,  harbour  virulent  diphtheria 
bacilli  in  their  throats.  If  their  resistance  is  lowered 
owing  to  any  of  the  causes  to  be  mentioned  below, 
the  balance  is  upset  by  the  defective  working  of 
the  patient's  immunising  mechanism,  and  he  begins 
to  exhibit  the  symptoms  of  the  disease.  After  a 
time,  if  the  infection  does  not  kill  him,  his  tissues 

6 


Introduction. 


respond  by  making  special  antibodies  and  the 
infecting  microbe  is  destroyed ;  or  he  may  only 
make  just  sufficient  to  antagonise  the  microbial 
poisons  so  that  there  is  an  exact  balance  between 
the  immunity  of  the  host  and  the  toxicity  of  the 
microbe,  the  microbe  is  not  killed  off,  and  is  capable 
of  giving  the  disease  to  another  person.  Such  cases 
are  also  common  after  typhoid  fever,  cholera,  and 
other  like  diseases. 

Another  instance  of  a  microbe  which  is  commonly 
saprophytic,  but  which  can  become  pathogenic  with 
facility,  is  that  constant  inhabitant  of  the  gastro- 
intestinal tract,  the  Bacillus  coli  communis. 

Turning  now  to  the  phenomena  of  immunity 
exhibited  by  the  higher  animals  to  microbial  disease, 
we  find  that  certain  species  or  individuals  are  not 
susceptible  to  certain  diseases.  For  instance,  the 
lower  animals  are  not  attacked  by  the  gonococcus 
or  by  syphilis  (except  when  artificially  infected  by 
the  latter),  while  man  does  not  get  distemper. 
Again,  certain  individuals  pass  through  violent 
epidemics  unscathed,  although,  as  we  have  seen, 
they  may  be  actually  harbouring  the  causative 
microbe.  Such  species  or  individuals  are  said  to  be 
'  naturally  immune.' 

This  natural  immunity  varies  with  different  condi- 
tions. Children,  as  a  rule,  are  more  susceptible  to 
measles  and  whooping-cough  than  adults.  There 
are  indications  that  sex  may  have  some  influence  ; 
thus,  the  resistance  of  females  to  infection  seems  to 
be  lowered  during  the  menstrual  period.  There  are 
certain  conditions  of  environment  which  notoriously 

7 


Therapeutic  Immunisation. 


lower  resistance  to  infection,  such  as  chills  caused 
by  wet  and  cold.  Draughts  invariably  cause  an 
attack  of  nasal  catarrh  in  some  people.  Alcohol, 
too,  lowers  the  vitality  by  dilating  the  superficial 
capillaries  and  causing  a  rapid  radiation  of  heat, 
and  probably  also  by  directly  affecting  the  immunis- 
ing mechanisms.  There  are  many  other  predisposing 
causes,  e.g.,  grief,  hunger,  fatigue,  bad  food,  bad 
smells  and  certain  systemic  diseases — for  instance, 
chronic  nephritis  and  diabetes :  tuberculosis  is  a 
frequent  terminal  event  in  the  latter  disease. 
Immunity  may  also  be  '  acquired  ' 

1.  By  an  attack  of  the  disease.  An  attack  of 
typhoid  fever  commonly  leaves  the  patient  immune 
for  a  number  of  years.  On  the  other  hand,  after  pneu- 
monia immunity  lasts  a  very  short  time  as  a  rule. 

2.  By  injecting  into  the  patient  the  blood  or 
blood  serum  of  an  animal  which  has  previously 
been  inoculated  with  the  disease.  In  this  case  the 
patient's  tissues  take  no  part  in  the  production  of 
the  antibodies  and  the  immunity  is  known  as  *  passive 
immunity  '  ;  such  immunity  is  used  for  the  prophy- 
laxis and  treatment  of  diphtheria  and  tetanus,  for 
instance. 

3.  By  the  patient's  tissues  being  stimulated  to 
take  an  active  part  in  the  production  of  antibodies. 
This  condition  is  known  as  *  active  immunity.'  It 
may  be  produced  in  several  ways  : — 

{a)  By  causing  an  unmodified  attack  of  disease. 
This  was  one  of  the  earliest  ways  of  combating 
small-pox,  one  patient  being  infected  from  another. 
It  was  given  up  owing  to  the  number  of  fatalities. 

8 


Introduction. 


(b)  By  causing  a  mild  attack  of  the  disease  with  a 
modified  virus.  Such  is  the  present  mode  of  inocu- 
lating against  small-pox,  the  virus  being  modified 
by  passage  through  the  calf.  Pasteur  used  cultures 
of  anthrax  bacilli,  grown  at  a  high  temperature 
and  so  modified  in  virulence,  for  the  prophylaxis  of 
this  disease  in  herds  and  flocks.  He  also  used  rabies 
virus,  modified  by  drying  for  different  periods. 
Haffkine's  cholera  vaccine  is  made  from  cultures 
grown  at  a  high  temperature,  viz.,  39  deg.  C. 

(c)  By  inoculating  the  patient  with  the  killed 
microbe  or  its  toxins.  This  method  is  used  both  for 
prophylaxis  and  treatment.  Wright  has  introduced 
a  typhoid  vaccine  for  prophylactic  purposes  ;  it  is 
extensively  used  with  most  satisfactory  results. 
The  vaccine  consists  of  virulent  typhoid  bacilli 
grown  in  broth  and  suspended  in  normal  salt 
solution  and  killed  by  heat  or,  preferably,  by 
antiseptics.  Haffkine's  plague  prophylactic  is 
vaccine  made  from  a  virulent  culture  of  the 
Bacillus  pestis  and  killed  by  heat.  There  can  be 
no  doubt  that  vaccines  will  be  and  ought  to  be 
more  extensively  used  for  prophylactic  purposes  ; 
for  instance,  the  children  of  tubercular  parents 
ought  all  to  be  inoculated  with  tubercuKn,  and 
people  who  have  recovered  from  a  disease,  such 
as  pneumonia,  which  leaves  them  open  to  another 
attack,  ought  to  be  immunised  against  the  special 
micro-organisms. 

For  purposes  of  treatment  vaccines  are,  at  present, 
our  most  powerful  weapon,  both  in  chronic  and  in 
many  acute  infections. 

9 


Therapeutic  Immunisation. 


After  an  injection  of  a  vaccine,  there  is  usually 
a  period  more  or  less  marked  in  which  the  patient's 
natural  resistance  to  that  particular  infection  is 
lowered  ;  this  is  known  as  the  '  negative  phase.' 
In  order  to  do  away  with  this,  or  greatly  modify  it, 
a  dose  of  specific  serum,  if  available,  is  given  just 
before  or  at  the  same  time  as  the  vaccine.  In  this 
way  the  patient  is  rendered  passively  immune  and 
also  actively  immune.  Such  a  condition  is  called 
'  mixed  immunity.' 

Already  the  fact  has  been  mentioned  that  not 
only  are  certain  individuals  immune  to  certain 
microbes,  but  certain  tissues  are  also.  Take,  for 
instance,  the  tissues  seldom  infected  by  the  tubercle 
bacillus.  This  organism  is  very  fond  of  the  bones, 
lungs,  etc.,  but  it  seldom  attacks  muscles.  The 
gonococcus  flourishes  as  far  as  the  openings  of  the 
Fallopian  tubes  into  the  peritoneal  cavity,  but  it 
seldom  causes  peritonitis.  This  is  known  as  '  local 
immunity,'  and  the  instances  given  are  of  '  natural ' 
local  immunity.  It  may  also  be  acquired,  tem- 
porarily at  any  rate.  For  instance,  it  is  quite  a 
common  experience  to  see  boils  retrogressing  in 
one  place  and  progressing  at  another,  and  erysipelas 
spreading,  while  the  tissues  behind  the  spreading 
edge  are  overcoming  the  infection.  Passive  or 
active  local  immunity  could  only  be  satisfactorily 
induced  artificially  in  many  cases  by  injecting  the 
serum  or  vaccine  into  an  artery  going  to  the  part, 
which,  as  far  as  I  know,  has  not  been  done.  In  some 
cases  passive  immunity  can  be  induced  by  the  local 
appHcation  of  the  serum,  as,  for  instance,  by  injecting 

10 


Introduction. 

anti-meningococcic  serum  into  the  spinal  canal  in 
epidemic  cerebro-spinal  meningitis. 

Antibacterial  serum  has  also  been  used  locally  in 
diphtheria,  and  antisera  also  in  inflammation  of  the 
stomach.  Vaccines  have  been  injected  subcutane- 
ously  in  such  a  position  that  the  lymphatics  draining 
that  area  pass  through  the  affected  part. 

When  the  different  mechanisms  of  immunity  are 
being  discussed  it  will  be  possible  to  consider  the 
relation  of  these  processes  to  those  of  ordinary 
tissue  digestion  as  far  as  we  know  them,  and  I  think 
it  will  be  found  that  the  ordinary  antiferments 
found  in  the  blood — for  instance,  antitrypsin— 
resemble  in  their  attributes  (for  we  do  not  yet 
know  their  chemical  composition)  antitoxins  ;  and 
that  the  process  of  digestion  of  foreign  proteins,  such 
as  foreign  red  blood  corpuscles  and  certain  microbes, 
resembles  very  closely  that  of  the  tissue  digestion 
of  carbohydrates  (glucose)  and  fats.  We  do  not 
yet  know  precisely  the  form  in  which  proteins  are 
absorbed  by  the  tissue  cells. 


II 


CHAPTER  II. 


TOXINS  AND  ANTITOXINS. 

Since  we  do  not  know  the  chemical  composition 
of  toxins  we  must  try  to  define  their  chemical 
position  by  their  attributes.  The  statement  was 
made  in  the  first  chapter  that  toxins  were  ferment- 
like substances  ;  the  reasons  for  this  statement 
must  be  considered  now. 

All  the  vital  activities  of  protoplasm,  even  tissue 
respiration,  have  been  referred  to  the  action  of 
ferments,  so  that  it  cannot  be  doubted  that  micro- 
organisms break  down  proteins,  carbohydrates  and 
other  similar  substances,  by  means  of  ferments, 
for  we  know  of  no  other  method  by  which  living 
protoplasm  can  effect  these  changes.  The  question 
is  whether  the  special  substances  which  some  of 
them  have  developed  and  which  are  able  to  attack 
the  living  protoplasmic  molecule  are  ferments  also. 

These  toxins  must  not  be  confused  with  poisonous 
substances  which  may  be  formed  by  the  breakdown 
of,  say,  a  protein  molecule,  such  as  peptone,  nitrites 
and  indole,  which  are  ordinary  products  of  meta- 
bolism. 

Like  ferments,  toxins  can  be  divided  into  two 
classes  :  (i)  The  exotoxins  are  soluble  and  can  be 
obtained  from  the  culture  medium  in  which  the 
microbe  is  grov/ing.  (2)  The  endotoxins  are  confined 
to  the  body  of  the  micro-organism,  no  toxin  being 
found  in  the  culture  medium. 

Exotoxins,  for  instance,  tetanospasmin,  the  toxin 
12 


Toxins. 


produced  by  the  tetanus  bacillus,  may  be  compared 
with  a  ferment  such  as  trypsin. 

The  trypsin  of  the  pancreas  breaks  down  the 
large  complex  non-diffusible  protein  molecules  in 
such  a  way  as  to  render  them  diffusible  and  capable 
of  serving  as  food  for  the  tissue-cells.  So,  too,  the 
toxin  breaks  down  the  large  living  protoplasmic 
molecule,  making  it  suitable  food  for  the  microbe. 
For  instance,  if  tetanus  spores  washed  free  from 
toxin  are  injected  into  an  animal,  the  spores  perish 
and  the  animal  does  not  develop  the  disease  ;  but 
if  some  toxin  is  injected  with  them  it  prepares  food 
for  the  spores  which  are  then  able  to  germinate  and 
to  produce  the  disease. 

Ferments  are  specific  in  their  action.  A  ferment 
that  hydrolyses  a  protein  will  not  hydrolyse  a  sugar, 
and  a  ferment  that  hydrolyses  one  sugar  will  not 
hydrolyse  another.  This  is  well  illustrated  by  the 
stereo-isomeric  sugars,  ^i-glucose  and  /-glucose. 
The  former  is  the  familiar  dextrose  or  grape  sugar, 
the  latter  is  said  not  to  occur  in  Nature.  They  only 
differ  from  each  other  in  the  arrangement  in  space 
of  their  constituuent  atoms.  This  is  illustrated  in 
their  graphic  formulae  : — 


HO— C— H 


H— C— OH 


COH 


COH 
H— d:— OH 
HO— C— H 


HO— C— -H 
CH2OH 


HO— C— H 


H— C— OH 

H— d:— OH 

('jHaOH 


^-glucose 


^f-glucose* 


13 


Therapeutic  Immunisation. 


The  rf-glucose  is  split  up  into  COg  and  HgO  by 
glycolytic  ferments  with  ease,  the  /-glucose,  if  at  all, 
with  difficulty.  Fischer  compares  the  action  of  a 
ferment  on  its  substrate  to  a  key  fitting  a  lock,  the 
opening  of  the  door  which  corresponds  to  the  lytic 
process  only  occurring  when  the  key  fits. 

The  combining  group  of  the  ferment  must  unite  with 
the  molecule  it  is  attacking  before  the  ferment  can 
act.  The  action  of  pepsin  on  fibrin  may  be  taken  as  an 
example.  If  fibrin  on  which  pepsin  is  acting  is  cooled 
to  a  low  temperature  (o  deg.  C),  then  thoroughly 
washed  with  ice-cold  water  to  remove  all  the  free 
ferment,  and  is  then  restored  to  the  proper  tem- 
perature (37  deg.  C),  digestion  continues  as  before, 
showing  that  the  pepsin  that  has  been  acting  has 
remained  in  chemical  combination  with  the  mole- 
cules of  fibrin.  Invertase,  a  ferment  which  hydro- 
lyses  cane  sugar,  has  also  been  shown  to  unite 
chemically  with  the  molecules  of  cane  sugar  before 
breaking  them  down.  In  the  same  way  a  toxin  does 
not  attack  the  molecules  of  a  living  cell  unless  it 
can  combine  with  them.  If  tetanospasmin  is 
injected  into  certain  animals  {e.g,,  the  tortoise),  it 
can  be  removed  months  afterwards  from  their  blood  ; 
it  has  not  been  able  to  combine  with  any  of  the  cells 
of  the  animal,  and  has  therefore  produced  no 
symptoms.  If,  however,  it  is  injected  into  a  sus- 
ceptible animal,  it  rapidly  combines  with  cells  of 
the  central  nervous  system,  producing  the  charac- 
teristic symptoms ;  so  strong  is  its  affinity  for  nervous 
tissue  that  emulsions  of  brain  substance  have  been 
injected  into  patients  suffering  from  tetanus  in 

14 


Toxins. 


order  to  neutralise  the  toxin  that  may  be  circulating. 
Hens  are  not  susceptible  to  tetanus  because  their 
general  tissues  have  an  affinity  for  the  poison  and 
so  take  it  up  before  it  can  reach  the  central  nervous 
system.  If  it  be  injected  directly  into  the  central 
nervous  system  of  the  hen  tetanus  develops. 

In  every  chemical  reaction  there  is  a  temperature 
at  which  the  chemical  change  takes  place  most 
rapidly,  and  ferments  and  toxins  are  no  exceptions 
to  this  rule.  As  we  have  seen,  pepsin  will  not  act 
on  fibrin  at  o  deg.  C,  the  optimum  temperature  for 
its  action  being  the  body  temperature.  Tetanolysin, 
a  haemolytic  substance  produced  by  the  tetanus 
bacillus,  unites  with  the  red  corpuscles  at  o  deg.  C, 
but  will  not  break  them  down  until  the  temperature 
is  raised  :  the  most  favourable  temperature  for  the 
action  being  the  body  temperature.  If  a  frog  is 
inoculated  with  tetanospasmin,  the  poison  dis- 
appears from  its  circulation,  but  the  animal  does  not 
develop  symptoms.  If,  however,  the  animal's  tem- 
perature is  raised  to  30  deg.  C.  for  some  days,  typical 
symptoms  of  tetanus  appear. 

It  thus  appears  that  both  ferments  and  toxins 
have  two  properties,  that  of  combining  and,  after 
the  union  has  taken  place,  of  producing  their 
characteristic  effects,  if  the  conditions  are  suitable. 
Erlich  has  given  names  to  these  two  groups  of  atoms 
of  the  toxin  and  enzyme  molecules.  The  combining 
group  he  calls  the  *  haptophore,'  the  active  group 
'  zymophore  '  or  '  toxophore.'  He  conceives  the 
atoms  of  the  protoplasmic  molecule  with  which  the 
haptophore  group  combines  to  be  Uke  the  side  chain 

15 


Therapeutic  Immunisation. 


of  a  benzene  nucleus,  and  he  calls  them  '  receptors/ 
This  is  known  as  the  '  side-chain  theory.' 

The  toxophore  group  can  be  destroyed  by  certain 
chemical  and  physical  means  without  interfering 
with  the  combining  faculties  of  the  haptophore 
group ;  indeed,  there  are  indications  that  the  com- 
bining powers  of  this  may  be  increased. 

Such  altered  enzymes  or  toxins  are  known  as 
zymoids  or  toxoids  respectively.  The  chief  methods 
of  producing  this  inactivation  are  the  action  of  heat, 
light,  oxygen  and  such  chemicals  as  iodine  and 
carbon  bisulphide.  Toxoids  will  cause  the  formation 
of  antitoxin  quite  as  well  as  toxins. 

Both  enzymes  and  toxins  are  precipitated  by 
the  agents  that  precipitate  proteins  and  destroyed 
by  the  agents  that  destroy  proteins.  And,  although 
it  is  extremely  hard  to  obtain  ferments  in  a  pure 
state  owing  to  the  fact  that  precipitated  protein 
absorbs  and  carries  down  any  ferments  and  toxins 
that  may  be  present,  yet,  the  purest  ferment  that 
has  been  obtained,  viz.,  pepsin  by  Pavlow's  method, 
has  a  protein-like  structure.  The  same  may  be  said 
of  ricin,  a  vegetable  toxin  which  is  obtained  from  the 
castor  oil  plant  and  which  acts  in  the  same  manner 
as  bacterial  toxins.  However,  recent  work  has  sug- 
gested that  the  proteolytic  ferments  and  toxins 
may  be  of  a  lipoid  nature,  or  attack  the  lipoid 
elements  of  the  protein  molecule,  the  suggestion 
being  made  that  the  protein  molecule  consists  of 
amino-acids  linked  together  by  means  of  lipoid 
elements.  If  these  are  removed  the  protein  molecule 
falls  to  pieces.    At  any  rate,  these  ferments  and 

i6 


Toxins. 


toxins  differ  from  the  higher  proteins  in  being  able 
to  pass  through  an  animal  membrane  or  a  Pasteur 
filter,  just  as  peptones  can.  They  also  induce  anti- 
bodies, which  are  different  to  those  induced  by  the 
higher  proteins. 

There  is  one  point  in  which  toxins  appear  to 
differ  from  enzymes.  The  latter,  at  any  rate  outside 
the  body,  can  go  on  acting  indefinitely  ;  for  when  an 
enzyme  has  broken  down  the  molecule  on  which  it 
is  acting,  it  is  set  free  to  attack  another  molecule. 
This  does  not  seem  to  be  the  case  with  toxins  ;  but 
then  toxins  are  not  attacking  inert  molecules,  but 
molecules  which  are  possessed  of  '  life,'  and  so  one 
would  expect  that  there  would  be  some  difference. 
And  again,  if  a  ferment,  such  as  trypsin,  is  injected 
into  the  circulation  so  as  to  be  under  the  same  condi- 
tions for  action  as  a  toxin,  it  is  likely  that  the  way 
in  which  it  acts  on  the  tissue  cells  is  similar.  At 
any  rate,  the  tissue  cells  respond  by  forming  similar 
antibodies  in  both  cases. 

Endotoxins. — The  majority  of  pathogenic  micro- 
organisms do  not  pour  forth  soluble  toxins  into  the 
culture  media  in  which  they  are  growing,  but  it  is 
found  that  the  bodies  of  the  microbes  themselves 
are  poisonous,  both  when  alive  and  when  dead. 

Just  as  we  have  compared  the  exotoxins  to  the 
soluble  ferments,  so  we  may  compare  the  endo- 
toxins to  the  intracellular  ferments  or  endoenzymes. 
As  mentioned  above,  all  the  activities  of  living  cells, 
both  of  anaboUsm  and  cataboUsm,  have  been  referred 
to  the  action  of  endoenzymes,  even  the  function  of 
respiration ;  so  that  it  is  not  surprising  that  the 


Therapeutic  Immunisation. 


microbial  cell  has  produced  a  ferment  that  will 
attack  living  jtissues,  on  which  it  has  to  live.  In 
this  they  are  not  unique,  for  do  not  cancer  cells 
and  the  syncytium  of  the  chorionic  villi  do  the 
same  ? 

Although  many  of  these  microbes,  e.g,,  the  typhoid 
bacillus,  the  pneumococcus,  the  cholera  vibrio,  do 
not  produce  soluble  toxins  in  vitro  under  ordinary 
circumstances,  yet  in  some  cases  they  can  be  made 
to  do  so  in  the  test  tube  by  special  means  and, 
undoubtedly,  some  of  them  do  so  in  the  body.  For 
instance,  Chantimesse  has  obtained  a  soluble  toxin 
from  the  typhoid  bacillus  by  growing  it  in  broth 
made  with  an  extract  of  the  spleen.    That  soluble 
toxins  are  produced  from  the  cholera  bacillus 
in  vivo  has  been  shown  by  Metchnikoff,  who  intro- 
duced the  virulent  cholera  vibrios  enclosed  in  a 
collodion  bag  into  the  peritoneal  cavity  with  the 
result  that  the  animal  died  of  cholera,  although  no 
vibrios  escaped.    The  production  of  toxins  soluble 
but  more  or  less  localised  to  the  region  in  which  the 
microbe  is,  owing  perhaps  to  the  comparatively 
small  amount  of  the  toxin  produced,  may  be  induced 
in  some  such  way  as  '  hormones  '  induce  the  secre- 
tion of  ferments  by  the  cells  of  glands,  e,g,,  just  as 
secretin  induces  the  secretion  of  the  pancreas.  The 
production  of  Chantimesse's  typhoid  toxin  would 
certainly  suggest  something  of  the  sort.    With  the 
same  object  in  view  microbes  have  been  grown  in 
the  blood  serum  of  an  immunised  animal,  so  that 
the  antibodies  contained  in  it  may  stimulate  the 
microbe  to  produce  more  toxin. 

i8 


Antitoxins. 


Antitoxins. 

As  we  have  seen,  toxins,  like  ferments,  induce 
when  injected  into  the  circulation  antibodies,  that 
is,  substances  which  antagonise  the  action  of  the 
ferment  or  toxin,  preventing  it  from  exercising  its 
characteristic  effect.  Such  antibodies  are  found 
normally  in  the  blood — for  instance,  antitrypsin ; 
and  there  can  be  little  doubt  that  antitoxins  are 
similar  substances.  Antitetanolysin  occurs  com- 
monly in  the  blood  of  horses  and  cattle,  in  whose 
intestines  the  tetanus  bacillus  is  a  common  parasite. 

These  antitoxins  or  antiferments  might  act  in 
two  ways,  viz.,  either  by  destroying  the  '  ergophore ' 
(zymo-  or  toxo-  phore)  group  of  the  toxin  molecule,  or 
else  by  uniting  with  the  haptophore  group,  and  thus 
preventing  the  union  of  the  toxin  with  the  receptors 
of  the  molecules  it  is  attacking.  The  latter  has  been 
found  to  be  the  case  ;  and  according  to  Ehrlich  the 
antitoxin  is  the  receptor  or  side-chain,  that  is,  the 
part  of  the  protein  molecule  with  which  the  toxin 
combines,  which  is  cast  off  into  the  blood  and 
tissue  fluids  and  there  unites  with  the  haptophore 
group  of  the  toxin  molecule. 

As  a  matter  of  fact  the  molecule  of  antitoxin  is 
much  larger  than  the  molecule  of  toxin,  and  it  is 
quite  possible  that  one  molecule  of  antitoxin  can 
neutraUse  many  molecules  of  toxin.  That  it  is 
much  larger  is  shown  by  the  fact  that  it  will  not  pass 
through  an  animal  membrane  or  gelatinised  Pasteur 
filter,  and,  as  we  know,  toxin  will.  Ehrlich  imagines 
the  production  of  antitoxin  somewhat  as  follows  ; 


Therapeutic  Immunisation. 


a  molecule  of  toxin  unites  with  a  receptor,  and  the 
molecule  of  protoplasm  finds  that  it  cannot  build 
up  the  toxin  molecule  into  its  substance  owing 
possibly  to  the  absence  of  a  suitable  endoenzyme 
for  its  destruction  ;  the  presence  of  the  indigestible 
molecule  interferes  with  the  nutrition  of  the  cell — 
that  is,  the  cell  is  poisoned.  In  order  to  get  rid  of 
the  indigestible  molecule  it  must  cast  off  the 
receptor  with  it,  for  the  two  are  chemically  united. 
The  protoplasmic  molecule  then  replaces  the  cast- 
off  receptor  by  a  number  of  similar  receptors,  which 
are  shed  into  the  tissue  fluids.  This  is  quite  similar 
to  the  process  which  we  imagined  to  take  place  in 
the  increase  of  toxicity  of  a  strain  of  microbes.  The 
amount  of  toxin  which  combines  with  the  living 
unit  must  not  be  so  great  as  to  interfere  with  its 
nutrition  to  such  an  extent  as  to  bring  that  nutri- 
tion to  a  standstill— that  is,  to  kill  the  unit.  The 
stimulus,  in  other  words,  must  be  submaximal. 

We  see,  therefore,  that  in  order  that  antitoxin 
may  be  formed  the  toxin  must  be  (i)  able  to  unite 
with  certain  units  of  the  living  molecule  ;  otherwise 
the  toxin  is  excreted  unaltered  and  sometimes,  as 
in  the  tortoise,  remains  so  in  the  circulation  for 
months  ;  (2)  that  the  living  unit  must  not  contain 
an  intracellular  ferment  for  its  digestion;  and  (3)  that 
the  living  unit  must  not  be  killed. 

Antitoxic  sera  for  the  treatment  of  human  beings 
are  as  a  rule  derived  from  the  horse,  and  for  the 
following  reasons  : — 

I.  It  can  give  a  large  supply  of  serum  without 
injury  to  itself. 

20 


Antitoxins. 


2.  The  serum  proteins  of  it  are  comparatively 
little  toxic  to  human  beings. 

3.  The  horse  is  susceptible  to  most  of  the  diseases 
for  which  we  desire  to  obtain  antisera. 

After  injecting  the  toxin,  as  a  rule  subcutaneously, 
there  is  a  latent  period  of  longer  or  shorter  duration. 
This  period  is  followed  by  a  'local'  reaction  con- 
sisting of  a  marked  swelling  and  induration  round 
the  site  of  the  injection,  and  a  *  general  reaction  '  of 
malaise,  loss  of  appetite  and  fever.    This  reaction 
lasts  for  from  hours  to  two  or  more  days,  according 
to  the  dose  and  the  individual  susceptibility  of  the 
animal.    This  period  of  reaction  corresponds  to  a 
period  in  which  the  resistance  of  the  animal  to  the 
disease  in  question  is  lowered — the  animal  is  said 
to  be  in  a  '  negative  phase  '  or  in  a  condition  of 
'  hypersusceptibility.'     Even  before  this  negative 
phase  has  passed  off  considerable  amounts  of  anti- 
toxin have  appeared  in  the  circulation.    This  may 
seem  paradoxical,  but  we  shall  see  later  on  that  in 
the  formation  of  immune  body  there  is  often  a 
qualitative  difference  in  the  immune-body  first 
formed  (see  p.  39).    In  the  same  way  the  early 
formed  antitoxin  may  not  be  so  efficient  as  that 
formed  later  on.   This  '  negative  phase  '  is  followed 
by  a  '  positive  phase  '  in  which  the  animal  has  an 
increased  resistance  to  the  disease  ;  and  this  is  found 
to  correspond  to  an  increase  in  the  amount  of  anti- 
toxin in  the  blood.   The  animal  is  given  increasing 
doses  of  toxin  during  the  positive  phases,  until  it 
develops  a  large  amount  of  antitoxin  and  can  stand 
large  doses  of  the  live  microbe  itself. 

21 


Therapeutic  Immunisation. 


The  amount  of  antitoxin  an  animal  can  produce 
varies  with  the  individual,  and  it  is  found  that  after 
a  certain  level  of  antitoxin  production  is  reached, 
larger  doses  of  toxin  will  not  further  increase  the 
amount  of  antitoxin  in  the  blood.  The  amount 
keeps  constant  for  a  longer  or  shorter  time,  then 
gradually  falls  until  there  is  no  antitoxin  in  the 
blood  at  all,  although  the  animal  is  quite  as  immune 
to  the  disease — indeed,  it  may  be  more  so.  After  a 
long  rest  such  an  animal  may  be  induced  to  form 
some  antitoxin  again,  but  comparatively  httle. 
EhrUch's  explanation  of  this  phenomenon  of 
immunity  without  the  presence  of  antitoxin  is  that 
the  susceptible  cells  no  longer  form  receptors  for 
the  toxin.  But  the  receptors  with  which  the  toxin 
originally  united  must  have  been  used  for  uniting 
with  food  atoms  of  some  kind,  and  it  seems  unlikely 
that  the  living  molecules  could  permanently  do  with- 
out these  receptors.  It  seems  more  in  accordance 
with  Ehrlich's  theory  of  nutrition  to  suppose  that 
the  living  units  have  developed  intracellular  fer- 
ments to  deal  with  the  toxin  so  that  it  is  no  longer 
necessary  for  them  to  cast  off  the  receptor-toxin 
combination;  therefore  the  Uving  units  no  longer 
receive  the  stimulus  which  induced  them  to  form  an 
abnormal  amount  of,  and  to  cast  off,  the  '  receptors.' 

The  period  of  hypersusceptibility,  the  negative 
phase,  has  given  a  lot  of  trouble  to  makers  of  anti- 
sera  ;  for  if  another  injection  is  given  during  this 
period  the  hypersusceptibility  is  further  increased 
and  the  animal  frequently  dies.  We  shall  see  later 
that  the  negative  phase  corresponds  to  a  fall  in  the 

22 


Antitoxins. 


phagocytic  power  of  the  leucocytes,  and  no  doubt 
of  the  other  phagocytic  cells  ;  there  is  also  a  leu- 
copenia,  at  any  rate,  in  the  peripheral  circulation. 
Probably  all  the  tissues  participate  in  this  lowering 
of  resistance. 

It  will  be  useful  to  state  some  of  the  devices  used 
for  modifying  this  period. 

1.  The  toxin  is  given  mixed  with  antitoxin,  or  a 
dose  of  toxin  given  in  one  place  and  antitoxin  in 
another.  There  is  thus  produced  a  condition  of 
'  mixed  '  immunity. 

2.  The  toxin  is  converted  into  toxoid  by  sulphur 
tetrachloride  or  iodine  in  a  solution  of  potassium 
iodide.  As  we  have  seen,  toxoids  are  excellent 
antigen. 

3.  What  might  be  called  specific  toxoids  are 
given.  The  bacillus — e.g.,  of  diphtheria — is  grown 
in  a  medium  to  which  a  large  amount  (15 — 30  per 
cent.)  of  horse  serum  has  been  added.  After  a 
time  the  culture  is  heated  to  65  deg.  C.  for  thirty 
minutes  and  then  filtered.  The  altered  toxin 
(toxoid)  gives  rise  to  a  general  but  no  local  reaction. 

There  are  many  theories  as  to  the  exact  way  in 
which  toxin  and  antitoxin  interact.  The  subject  is 
a  very  complex  one  and  need  only  be  treated  of 
superficially  here. 

Diphtheria  toxin  is  considered  of  normal  strength 
when  c.c.  will  kill  a  guinea-pig  weighing  250 
grammes  in  about  four  days  ;  this  is  the  '  mini- 
mum lethal  dose  '  (M.L.D.)  of  the  toxin.  A  unit  of 
diphtheria  antitoxin  is  that  amount  which  will 
neutralise  100  M.L.D. ,  that  is,  i  c.c.  of  it.  The 

23 


Therapeutic  Immunisation. 


quantity  of  serum  that  does  this  varies  with  each 
sample  of  serum ;  i  c.c.  of  a  serum  may  contain  any- 
thing from  300  to  1,000  units  or  more.  So  for  testing 
purposes  the  serum  is  diluted. 

The  union  of  toxin  and  antitoxin  is  a  complex 
one,  and  it  is  not  easy  to  account  for  all  the  phe- 
nomena. For  instance,  take  a  serum  i  c.c.  of  which 
neutralises  100  minimum  lethal  doses  of  toxin,  then 
one  would  expect  that  if  j^(5%  c.c.  of  antitoxin  were 
added  to  the  100  M.L.D.  of  toxin  i  M.L.D.  would  be 
left  free  and  the  animal  would  die  in  the  normal  time 
if  the  mixture  were  injected.  But  it  doe3  not ;  and 
it  is  not  until  the  antitoxin  in  the  mixture  is  reduced 
to  about  c.c.  that  i  M.L.D.  is  set  free  and  the 
animal  dies. 

Again,  if  i  c.c.  of  antitoxin  {i.e.,  1  unit)  is  added  by 
degrees  to  100  M.L.D.  of  toxin,  no  diminution  of 
toxicity  is  noticed  until  ^^.s^  c.c.  is  added,  which 
means  that,  if  less  than  this  '25  c.c.  is  added,  100 
lethal  doses  remain  free  and  the  antitoxin  will  kill 
100  guinea-pigs. 

Ehrlich  supposes  that  toxin  and  antitoxin  react 
like  a  strong  acid  and  a  strong  base,  and  accounts 
for  the  above  phenomena  by  presuming  the  presence 
of  other  substances  in  addition  to  the  true  toxin. 
In  the  first  case,  just  mentioned,  he  supposes  the 
presence  of  a  substance  ioxon,  which  is  not  all  com- 
bined until  more  than  c.c.  of  antitoxin  are  added  ; 
and  in  the  second  case  he  supposes  the  presence  of 
prototoxoid ,  a  non-toxic  substance,  which  has  a 
greater  affinity  for  antitoxin  than  toxin  has,  and 
must  all  be  combined  before  any  toxin  can  be 

24 


Antitoxins. 


neutralised.  The  composition  of  the  toxin  might 
be  represented  diagrammatically  thus  : — 


Proto- 
toxoid. 


Toxin. 


Toxon. 


It  was  found,  however,  that  there  were  many 
other  anomalies  of  combination  in  particular  cases. 
For  each  Ehrlich  supposes  the  presence  of  a  new 
substance.  These  need  not  be  mentioned  here. 
Toxon  he  supposes  to  be  the  cause  of  post-diph- 
theritic paralysis. 

Arrhenius  and  Madsen  consider  that  the  inter- 
action of  toxin  and  antitoxin  is  like  that  of  a  weak 
acid  and  a  weak  base,  and  conforms  to  the  law  of 
mass  action.  They  take  as  an  example  the  inter- 
action of  alcohol  and  acetic  acid.  In  such  a  mixture 
there  is  always  some  free  alcohol  and  free  acid  as 
well  as  the  combination  of  both,  viz.,  ethyl  acetate, 
and  the  action  is  a  reversible  one.  Similarly,  in  a 
mixture  of  toxin  and  antitoxin  there  will  always  be 
free  toxin  and  antitoxin  and  the  combination  of  both. 
It  is  well  known  that  the  reaction  of  antigen  and 
ferment  is  a  reversible  one. 

There  are  certain  facts  for  which  this  theory  would 
well  account.  For  instance,  for  the  fact  that  active 
immunity  can  be  produced  by  a  mixture  of  toxin 
and  antitoxin,  that  small  doses  of  toxin-antitoxin 
are  innocuous  while  large  doses  may  be  fatal,  and 
that  a  similar  mixture  may  be  fatal  to  one  animal 
and  not  to  another.  It  would  further  explain  the 
death  of  an  animal  from  the  effects  of  a  toxin 


25 


Therapeutic  Immunisation. 


when  the  animal  akeady  has  some  antitoxin  in  his 
blood. 

Blitz  regards  the  interaction  as  one  of  adsorption 
between  colloids,  while  Bordet  thinks  it  like  the 
absorption  of  stain  by  a  tissue — the  addition  of 
antitoxin  rendering  the  whole  toxin  less  toxic. 
BUtz's  hypothesis  is  probably  nearest  the  truth. 

We  need  not  discuss  the  matter  further.  It  is  only 
necessary  to  realise  that  toxin  and  antitoxin  do 
unite  and  that  the  toxin  molecule  is  thus  rendered 
harmless. 

Now  what  is  the  source  of  the  antitoxin  ?  From 
theoretical  considerations  it  would  appear  that  any 
cell  with  which  the  toxin  combines  without  destroy- 
ing it  can  produce  and  cast  off  receptors,  that  is, 
antitoxin.  Ehrlich  at  first  supposed  that  antitoxin 
was  only  produced  by  the  susceptible  cells — for 
instance,  tetanus  antitoxin  by  nerve-tissue  cells. 
It  is  probable,  however,  that  less  poisoned  cells 
would  be  in  a  better  position  to  produce  the  anti- 
substance,  and  that  certain  cells  whose  business  it  is 
to  deal  with  invading  micro-organisms  would  pro- 
duce more.  It  is  found  that  more  antitoxin  is  pro- 
duced if  the  toxin  is  injected  subcutaneously  than 
if  injected  intraperitoneally,  and  more  if  injected 
intraperitoneally  than  if  injected  intravenously — 
the  same  is  true  of  certain  other  anti-substances,  such 
as  complement  and  opsonins.  It  would  thus  appear 
that  the  subcutaneous  cells  may  produce  more 
antitoxin  than  the  peritoneal  endothelium,  and  these 
cells  than  the  vascular  endotheHum.  However, 
other  factors  may  yet  be  discovered  to  account 

26 


Antitoxins. 


for  these  phenomena.  Some  facts  point  to  the 
leucocytes  as  a  great  source  of  antitoxin.  When  an 
animal  is  injected  with  a  toxin,  it  has  a  very  marked 
effect  on  the  conduct  of  the  leucocytes,  especially 
the  polynuclears.  If  the  dose  is  an  overwhelming 
one,  there  is  a  permanent  leucopenia  in  the  peri- 
pheral circulation  until  death.  If  the  dose  is  non- 
lethal,  there  is  at  first  a  leucopenia,  followed,  as  the 
negative  phase  passes  off  and  the  positive  phase 
comes  on,  by  a  leucocytosis.  During  the  peripheral 
leucopenia,  as  Andrews  has  shown,  the  leucocytes 
are  concentrated  in  the  internal  organs,  the  liver, 
the  spleen,  and  especially  in  the  lungs.  He  suggests 
that  these  cells  are  recuperating,  especially  in  the 
lungs.  The  increase  in  the  number  of  leucocytes 
runs  parallel  with  the  increase  of  the  amount  of 
antitoxin.  Metchnikoff  has  shown  that  if  after 
injecting  a  fowl  with  tetanospasmin  an  aseptic 
exudate  is  produced,  the  toxin  can  be  recovered 
from  the  leucocytes  in  it.  So  that  since  the  leuco- 
cytes take  up  the  toxin  they  must,  if  they  are  not 
killed,  produce  a  substance  to  neutralise  it.  More- 
over, we  shall  see  later  that  leucocytes  ingest  live 
micro-organisms  and  digest  them,  and  so  must  be 
able  to  produce  antibodies  to  their  toxins.  Indeed, 
we  should  expect  cells  with  such  functions  to  be 
specially  facile  at  producing  such  bodies.  We  may 
conclude,  then,  that  phagocytic  cells  probably 
produce  a  large  amount  of  antitoxin.  We  have 
already  seen  that  tissue  cells  themselves  can  become 
immune  in  erysipelas  and  furunculosis. 

It  is  likely  that  such  an  organ  as  the  liver,  the  cells 
27 


Therapeutic  Immunisation. 


of  which  have  various  activities,  and  which  is  always 
receiving  small  doses  of  bacterial  toxins  from  the 
alimentary  canal,  would  be  able  to  produce  anti- 
toxin with  ease. 

We  must  not  forget  that  small  doses  of  toxin  may 
be  dealt  with  without  invoking  much  special  aid. 
If  a  small  dose  is  injected  there  is  almost  at  once  an 
increased  blood  supply  to  the  part,  which  dilutes 
the  toxin  and  thus  renders  it  less  toxic  for  individual 
cells,  and  possibly  converts  it  by  its  oxidising  powers 
into  the  harmless  antigen  toxoid. 


28 


CHAPTER  III. 


BACTERIOLYSIS  AND  PHAGOCYTOSIS. 

The  way  in  which  the  animal  organism  deals  with 
the  microbial  cells  must  now  be  considered. 

There  are  two  ways,  either  of  which  may  act  alone, 
or  they  may  both  act  together  in  any  given  case. 

In  the  first  the  micro-organisms  are  broken  up 
into  their  elements  by  the  ferments  or  ferment-like 
substances  in  the  body. 

In  the  second  way  they  are  taken  up  and  digested 
by  the  phagocytic  cells  of  the  body,  viz.,  the  leuco- 
cytes, especially  the  polynuclear  neutrophiles  ;  the 
endothelial  cells  of  the  blood-vessels,  lymphatics 
and  serous  cavities  ;  the  epitheUal  plates  of  the  lung 
alveoU  ;  the  star  cells  in  the  liver  ;  large  phagocytic 
cells  in  the  spleen  and  bone  marrow,  and  so  on. 

The  first  method  is  called  bacteriolysis.  It  was 
first  observed  by  Pfeiffer,  who  found  that  when 
cholera  vibrios  were  injected  into  the  peritoneal 
cavity  of  immunised  guinea-pigs  they  were  killed 
and  dissolved  very  quickly,  first  becoming  immobile, 
then  sweUing  up  into  spherical  masses,  which  became 
gradually  smaller  until  they  disappeared.  Bordet 
furnished  the  explanation  of  this ;  he  found  that  if 
cholera  vibrios  were  added  to  the  fresh  serum  of  an 
immunised  animal  they  became  dissolved,  but  if  the 

29 


Therapeutic  Immunisation. 


serum  was  first  heated  to  56 — 60  deg.  C,  no  solution 
of  the  vibrios  took  place,  but  that  if  to  this  mixture 
of  heated,  and  thus  inactivated,  immune  serum  a 
little  fresh  serum  from  a  normal  animal  was  added, 
solution  of  the  microbes  took  place  as  before.  There 
must,  therefore,  have  been  two  substances  present, 
one  of  which  only  occurs  in  the  serum  of  an  immu- 
nised animal  and  which  is  not  destroyed  by  heating 
to  60  deg.  C,  and  the  other  which  occurs  in  the  serum 
of  normal  animals  and  is  destroyed  by  heating  to  this 
temperature.  The  first  is  said  to  be  '  heat-stable/ 
and  is  called  variously  '  immune-body,'  '  ambo- 
ceptor,' '  substance  sensibilisatrice.' 

The  second  substance  is  said  to  be  '  heat-labile/ 
and  is  called  alexin  or  complement. 

Bordet  calls  the  heat-stable  substance  '  substance 
sensibilisatrice,'  because  he  thinks  that  it  sensitises 
the  microbes  and  so  enables  the  alexin  or  comple- 
ment to  act  on  it.  Bordet  also  found  that  the  same 
kind  of  thing  occurred  if  red  corpuscles  of  another 
animal  were  used  as  antigen,  and  much  research 
work  on  the  phenomena  of  lysis  has  been  carried  out 
on  red  blood  corpuscles.  For  instance,  if  a  rabbit  is 
injected  with  guinea-pig's  corpuscles  it  will  develop 
substance  sensibilisatrice,  and  if  guinea-pig's  cor- 
puscles are  added  to  the  fresh  immune  serum  they 
undergo  lysis  (haemolysis),  the  haemoglobin  being 
liberated.  If  this  serum  had  been  previously  heated 
to  60  deg.  C.  no  haemolysis  took  place  until  a  little 
fresh  normal  serum  had  been  added. 

Bordet,  as  we  have  seen,  thinks  the  heat-stable 
substance  acts  as  a  sensitising  agent,  which  further 

30 


Bacteriolysis  and  Phagocytosis. 


can  become  detached  after  the  complement  has 
united  with  the  antigen.  EhrUch,  on  the  other 
hand,  thinks  the  heat-stable  substance  acts  as  an 
intermediate  link  between  receptor  and  complement 
and  calls  it  amboceptor* 

The  heat-stable  and  heat-labile  substances  will 
be  referred  to  hereafter  as  '  immune-body  '  and 
'  complement '  respectively ;  the  term  '  immune- 
body  '  does  not  commit  one  to  any  particular 
theory. 

Immune-body  becomes  attached  to  the  receptors 
of  the  microbes  or  red  corpuscles,  for  if  either  are 
mixed  with  an  inactivated  immune  serum  or  with 
an  active  serum  at  o  deg.  C.  and  are  then  centrifuged 
and  washed  with  normal  solution,  the  corpuscles 
appear  unchanged,  but  if  after  suspending  them  in 
normal  saline  solution  complement  is  added  haemo- 
lysis takes  place.  In  this  experiment  Ehrlich  showed 
that  the  corpuscles  had  removed  all  the  immune- 
body,  so  that  if  more  corpuscles  were  added  to  the 
original  serum  they  were  not  sensitised. 

Ehrlich  thus  conceives  that  immune-body  had 
two  haptophore  or  combining  groups,  one  which 
unites  with  the  cell-receptors  the  '  cytophile ' 
haptophore,  the  other  with  the  complement  the 
*  complementophile  '  haptophore.  He  thinks  once 
the  combination  of  receptor,  immune-body  and 
complement  has  taken  place  that  it  is  permanent, 
and  that  even  after  haemolysis  immune-body  cannot 
be  recovered  or  set  free  again. 

It  has  been  proved,  however,  that  a  certain  amount 
of  immune-body  can  be  detached  before  and  after 

31 


Therapeutic  Immunisation. 


haemolysis,  which  would  tend  to  support  Bordet's 
ideas. 

Complement  like  toxin  has  a  combining  (hapto- 
phore)  group  and  a  zymophore.  This  latter  can  be 
inactivated  by  heat,  light,  oxidising  agents,  iodine, 
and  sulphur  tetrachloride,  and  thus  the  complement 
is  converted  into  complement oid,  just  as  toxin  can 
be  converted  into  toxoid ;  indeed,  complement  has 
been  called  '  animal  toxin.' 

This  complementoid  can  unite  with  the  immune 
body  and  so  interfere  with  lysis  by  keeping  out 
complement.  Ehrlich  thinks  that  complement  can 
combine  freely  with  immune-body  when  it  is  not 
attached  to  a  receptor.  Bordet  denies  this.  Recent 
work  has  demonstrated  that  complement  can  itself 
be  further  subdivided  into  two,  but  it  is  unnecessary 
for  our  purpose  to  complicate  the  matter  further. 

Complement  can  combine  directly  with  antigen 
at  a  suitable  temperature  and  the  union  is  a  firm 
one,  but  no  lysis  occurs  even  if  immune-body  is 
subsequently  added.  As  we  shall  see  presently, 
microbes  are  thus  prepared  for  ingestion  by 
phagocytes. 

I  have  stated  advisedly  that  these  substances, 
viz.,  immune-body  and  complement,  are  ferments, 
for  the  way  in  which  the  solution  of  these  masses  of 
foreign  protein  takes  place  is  exactly  the  process  by 
which  carbohydrates  and  fats  are  split  up  in  the 
tissues,  the  tissue-cells  providing  the  complement- 
like part  and  the  pancreas  being,  at  any  rate,  the 
chief  source  of  the  immune-body-like  part ;  these 
have  been,  in  this  connection,  called  '  ferment '  and 


32 


Bacteriolysis  and  Phagocytosis. 


'  coferment '  respectively.  We  have  no  accurate 
information  as  to  how  the  large  and  complicated 
protein  molecule  is  broken  down  by  the  tissue-cells, 
but  I  think  this  process  of  bacteriolysis  and  haemo- 
lysis furnishes  a  clue  to  what  takes  place  and  would 
suggest  the  method  of  metabolism  of  all  three 
substances  in  the  tissues  is  similar.  It  would  also 
suggest  that  a  chief  course  of  '  immune-body  '  for 
bacteriolysis  is  the  same  as  the  source  of  the  co- 
ferment  for  carbohydrates  and  fats,  and  this  would 
tend  to  be  confirmed  by  certain  phenomena  which 
take  place  on  inoculation  of  bacterial  vaccines  into 
people  with  diabetes  where  the  cells  of  the  pancreas 
which  produce  the  coferments  are  destroyed  or  not 
functioning  properly. 

The  immune-body  is  a  strictly  specific  substance  ; 
that  produced  by  the  stimulus  of  one  antigen  will 
act  on  that  substance  and  no  other.  In  contrast  to 
it  complement  is  much  more  feebly  specific — in  fact, 
many  deny  that  it  has  any  specificity  at  all  ;  they 
say  that  if  an  antigen  is  sensitised,  practically  any 
complement  will  unite  and  act.  It  appears,  however, 
that  there  is  a  feeble  specificity,  for  if  sensitised 
antigen  is  added  to  fresh  serum  a  certain  fraction  of 
the  complement  contained  in  it  is  attached  quicker 
than  the  rest,  but  that  eventually  the  whole  comple- 
ment is  fixed.  The  amount  of  this  more  specific 
complement  is  increased  temporarily  during  the 
process  of  immunisation  of  an  animal  with  any  given 
antigen.  Muir  has  shown  that  complement  derived 
from  certain  animals  absolutely  refuses  to  act  with 
immune-body  produced  from  certain  other  animals ; 

33  ' 


Therapeutic  Immunisation. 


for  instance,  horse's  complement  will  not  haemolyse 
ox*s  corpuscles  when  the  immune-body  for  them  has 
been  produced  by  the  rabbit. 

This  fixation  of  complement  to  antigen  by 
immune-body  is  utilised  for  diagnostic  purposes  ; 
for  if  antigen,  heated  patient's  serum  and  comple- 
ment are  mixed  and  incubated  together  and  the 
complement  becomes  fixed,  then  immune  body  for 
that  particular  antigen,  e,g,,  the  tubercle  bacillus,  is 
present  in  the  patient's  serum,  and  so  that  patient  is 
suffering  or  has  suffered  from  that  particular  infec- 
tion. The  effect  of  the  immune-body-complement 
combination  on  the  microbe  in  many  cases  does  not 
produce  lysis  of  it,  but  kills  it.  This  is  spoken  of  as 
a  '  bactericidal '  action. 

The  second  way  in  which  living  microbes  are 
disposed  of  by  the  body,  viz.,  phagocytosis,  was  first 
observed  by  Metchnikoff  in  the  amoeba,  which  he 
watched  engulfing  and  digesting  bacteria ;  he  also 
described  a  similar  process  taking  place  in  Daphnia, 
a  small  crustacean,  when  infected  by  the  spores  of  a 
yeast  Monospora,  the  immunity  of  the  animal  to  the 
infection  depending  on  the  ingestion  and  digestion 
of  the  infecting  micro-organism  by  the  animal's 
leucocytes.  He  found  that  this  method  of  removal 
of  not  only  living  organisms,  but  also  of  all  sorts  of 
foreign  materials,  which  had  got  into  the  body, 
occurred  throughout  the  animal  kingdom,  and  came 
to  the  conclusion  that  the  processes  of  immunity 
were  the  processes  of  nutrition,  a  truth  which  has 
become  and  is  becoming  more  and  more  clear  as  our 
knowledge  of  the  processes  of  nutrition  increases. 

34 


Bacteriolysis  and  Phagocytosis. 


Leishman,  Wright  and  Douglas,  and  following 
them  many  others,  have  worked  out  the  details  of 
this  process  of  phagocytosis  and  have  demonstrated 
that  in  the  case,  at  any  rate,  of  pathogenic  micro- 
organisms, a  certain  preparation  of  the  microbe  is 
necessary  before  ingestion  by  the  phagocytic  cell 
can  take  place. 

Leishman  mixed  blood  with  a  suspension  of  micro- 
organisms in  normal  saline  solution,  incubated  the 
mixture  under  cover  glasses  in  a  moist  chamber, 
then  made  smears  of  the  incubated  mixture,  stained 
the  films  and  counted  the  number  of  microbes  in  a 
certain  number  of  polynuclear  leucocytes  and  took 
the  average.  By  dividing  the  average  number 
ingested  by  the  leucocytes  in  the  blood  from  a 
normal  person  into  that  given  by  the  blood  from  an 
infected  person,  he  obtained  what  he  called  the 
'  phagocytic  index.' 

Wright  and  Douglas,  working  with  staphylococci, 
improved  the  technique  by  incubating  the  mixture 
in  capillary  tubes,  and  by  separating  the  elements 
involved  in  the  experiment,  found  that  if  the  leuco- 
cytes were  washed  free  from  serum  before  being 
mixed  and  incubated  with  the  microbial  suspension, 
little  or  no  phagocytosis  took  place,  so  that  there 
must  be  some  substance  in  the  serum  which  either 
stimulated  the  leucocytes  to,  or  prepared  the 
microbes  for,  phagocytosis.  They  showed  that  the 
substance  acted  in  the  latter  way,  and  they  called  it 
'  opsonin,'  from  the  Latin  word  opsono — I  prepare 
food  for  table.  They  further  found  that  if  the  serum 
was  first  heated  to  56 — 60  deg.  C.  before  being  used  in 

35 


Therapeutic  Immunisation. 


the  experiment,  little  or  no  phagocytosis  took  place, 
and  they  described  the  opsonin  as  being  heat-labile. 
They  found,  too,  that  this  heat-labile  opsonin  rapidly 
disappeared  on  keeping,  on  being  exposed  to  sun- 
light and  by  the  action  of  chemical  agents.  By 
means  of  their  technique  they  were  able  to  follow 
the  fluctuations  of  the  opsonin  content  of  the  serum 
under  varying  conditions,  and  by  dividing  the 
average  number  of  microbes,  opsonised  with  normal 
serum,  taken  up  by  leucocytes  into  the  average 
number  taken  up,  which  had  been  opsonised  by  a 
patient's  serum,  they  contained  what  they  called  the 
'  opsonic  index.'  For  instance,  the  average  number 
taken  up  when  prepared  by  the  normal  control  serum 
might  be  8,  while  when  prepared  by  the  patient's 
serum  it  might  be  4,  then  the  '  opsonic  index  ' 
would  be  .5.  It  was  found  that  an  index  falling 
between  -8  and  i-2  might  be  considered  normal,  and 
that  if  a  patient  was  infected  with  a  given  organism 
this  opsonic  index  to  it  frequently  lay  outside  these 
limits,  being  either  low  or  high,  or  fluctuating  from 
subnormal  to  supranormal.  It  was  found,  too,  that, 
in  such  a  disease  as  pneumonia,  the  index,  which 
during  the  acute  stages  was  subnormal,  would  rise 
suddenly  very  high  just  before  the  crisis.  In  a 
subsequent  chapter  I  shall  refer  to  the  effect  of 
inoculation  on  the  opsonic  content  of  the  blood. 

Whilst  studying  the  opsonising  properties  of  com- 
mercial anti-staphylococcic  and  anti-streptococcic 
sera  I  found  that,  although  they  might  contain  none 
of  the  heat-labile  opsonin  described  by  Wright  and 
Douglas,  and,  therefore,  would  produce  no  opsonisa- 

36 


Bacteriolysis  and  Phagocytosis. 


tion  by  themselves,  yet  if  some  fresh  normal  serum 
was  added  to  them  much  greater  phagocytosis  was 
brought  about  than  by  the  normal  serum  by  itself.  I 
found,  too,  that  the  substance  in  the  immune  sera 
producing  this  effect  was  not  destroyed  by  heating 
to  60  deg.  C,  and  I  suggested  that  in  these  sera 
the  greater  opsonisation  was  produced  by  the  inter- 
action of  two  substances  just  as  in  the  case  of  bac- 
teriolysis— in  short,  that  heat-labile  opsonin  was  com- 
plement, and  that  the  heat-stable  was  immune-body. 
Subsequent  work  by  others  has  confirmed  this  work, 
and  it  is  certain  that  this  is  one  of  the  methods  of 
opsonisation  in  immune-serum.  I  found,  too,  that 
there  was  a  small  amount  of  this  immune-body  to 
staphylococci  and  streptococci  in  my  own  and  other 
human  sera,  and  this  is  not  surprising,  since  few 
human  beings  escape  invasion  by  these  common 
pathogenic  organisms. 

Again,  Neuf eld,  working  with  the  serum  of  rabbits 
very  highly  immunised  against  virulent  streptococci, 
found  that  there  was  a  substance  in  it  which  was  not 
destroyed  by  heating  to  60  deg.  C,  which  would 
prepare  the  streptococci  directly  for  phagocytosis 
without  the  help  of  any  heat-labile  substance.  He 
called  this  substance  '  bacteriotropin,'  a  term  which 
has  been  more  recently  applied  to  anti-microbial  sub- 
stances in  general.  This  *  immune-opsonin,'  as  it 
is  called,  is  generally  considered  to  be  identical  with 
immune-body,  but  I  consider  it  far  more  likely  to 
be  anti-endotoxin,  for  it  occurs  in  the  sera  of  highly 
immunised  animals  and  complement  has  no  part  in 
its  action ;  and  further  it  seems  reasonable  to  suppose 

37 


Therapeutic  Immunisation. 


that  if  the  toxins  of  the  microbe  were  neutralised 
phagocytosis  would  readily  take  place.  The  fact 
that  diphtheria  antitoxic  serum,  which  may  contain 
no  heat-labile  opsonin  but  large  amounts  of  anti- 
toxin, is  a  powerful  opsonising  serum  would  tend  to 
confirm  this  view. 

What  I  have  said  above  as  to  the  specificity  of 
complement  applies  to  heat-labile  opsonin,  that  is, 
it  is  feebly  specific,  a  sensitised  antigen  removing 
all  the  opsonin  (as  well  as  the  complement,  for  they 
disappear  together),  but  some  of  it  is  attached 
quicker  than  the  rest.  The  inoculation  of  a  given 
antigen  produces  a  temporary  increase  of  this  more 
specific  heat-labile  opsonin.  On  the  other  hand,  the 
immune-body-like  opsonin  and  the  antitoxin-like 
immune-opsonin  are  absolutely  specific,  just  as 
immune-body  is  and  antitoxin  is. 

I  conceive  that  the  difference  between  the  opsonisa- 
tion  in  normal  and  immune-serum  is  this,  that  when 
a  phagocyte  takes  up  a  microbe  prepared  with  heat- 
labile  opsonin,  it  may  be  able  to  digest  it,  but  we 
know  very  often  it  cannot,  but  is  destroyed  by  the 
toxin  of  the  microbe,  which  microbe  may  thus  be 
deposited  in  some  place  where  it  becomes  a  grave 
source  of  danger  to  its  host  (this  is  certainly  one 
of  the  ways  virulent  microbes  gain  the  interior  of 
the  body),  while  in  the  case  of  the  microbe  which 
has  been  prepared  by  the  specific  opsonising  sub- 
stances the  phagocyte  can  ingest  and  certainly 
digest  it. 

From  the  point  of  view  of  prophylaxis  and  treat- 
ment the  induction  of  these  specific  antibodies  is  of 

38 


Bacteriolysis  and  Phagocytosis. 

the  utmost  importance  for  the  production  of  any 
kind  of  permanent  immunity. 

They  can  be  increased  to  a  very  high  degree  by 
steadily  increasing  the  dose  of  microbial  suspension 
during  positive  phases.  The  upper  limit  varies  with 
the  individual. 

It  has  been  found  that  the  immune-body  that 
first  appears  in  the  process  of  immunisation  is  of 
poorer  quality  than  that  produced  later. 

It  must  not  be  thought,  however,  that  the  quality 
and  quantity  of  the  leucocytes  is  of  no  importance  in 
the  matter.  Frequently  one  finds  in  opsonic  estima- 
tions that  while  the  majority  of  polynuclear  leuco- 
cytes have  taken  up  few  microbes,  others  will  be 
found  crammed  with  them,  indicating  a  marked 
difference  in  the  phagocytic  capacity  of  individual 
leucocytes.  It  has  also  been  found  that  using  the 
same  serum  and  bacterial  suspension  leucocytes  from 
different  individuals  differ  in  their  phagocytic 
capacity.  It  is  well  known  that  it  is  lowered  in 
certain  diseases,  such  as  spleno-meduUary  leukaemia. 
These  observations  have,  of  course,  only  been  made 
with  leucocytes,  but  without  doubt  the  other 
phagocytic  cells  vary  in  their  capacity  in  different 
individuals. 

Moreover,  of  the  leucocytes  themselves,  for  most 
microbes  the  polymorphonuclear-neutrophile  leuco- 
cytes are  by  far  the  most  active  phagocytes,  while 
the  eosinophile  cells  are  the  least,  the  mononuclear 
taking  an  intermediate  position. 

Another  important  factor  for  successful  opsonisa- 
tion,  as  for  all  ferment  and  anti-ferment  action,  is 

39 


Therapeutic  Immunisation. 


the  reaction  and  salt  content  of  the  medium  in  which 
the  action  is  taking  place. 

It  has  been  shown  that  if  the  reaction  of  the 
medium  is  made  slightly  acid  to  litmus,  phago- 
cytosis is  greatly  reduced  and  an  increased  amount  of 
acid  totally  inhibits  it.  The  most  favourable  reaction 
is,  of  course,  the  faintly  alkaline  reaction  of  the 
normal  blood.  This  may  be  a  factor  to  be  reckoned 
with  and  corrected  in  conditions  of  acidosis,  as  in 
fevers  and  in  such  diseases  as  rheumatism,  gout 
and  diabetes.  I  have  noticed  abnormal  reactions, 
after  inoculation  with  vaccines,  in  patients  suffering 
from  marked  acidosis  in  diabetes.  Acute  pyeUtis 
has  rapidly  cleared  up  when  the  urine  has  been 
rendered  alkaline,  and  in  treating  urinary  infections 
with  vaccines  the  urine  must  be  rendered  alkaline 
during  the  treatment,  unless  it  is  contraindicated 
by  the  presence  of  alkaline  phosphate  calcuU, 
where  the  urine,  owing  to  decomposition,  is  alkaline 
already. 

Too  strong  a  salt  solution  inhibits  opsonisation 
under  experimental  conditions,  and  it  is  probable 
that  in  both  lysis  and  opsonisation  the  presence  of 
lime  salts  is  essential. 

There  remains  the  question  whether  the  antibodies 
mentioned  are  present  in  the  whole  blood  as  they 
are  in  serum. 

It  has  been  shown  that  the  serum  that  first  is 
squeezed  out  when  the  clot  begins  to  contract  is 
much  poorer  in  opsonin  and  complement  than  that 
which  comes  out  later,  and  it  has  been  found  that 
very  little  phagocytosis  took  place  when  staphylo- 

40 


Bacteriolysis  and  Phagocytosis. 


cocci  were  injected  into  a  surviving  heart  in  which 
no  clotting  took  place.  When  virulent  microbes  are 
injected  directly  into  the  circulation,  practically  no 
phagocytosis  takes  place  in  the  circulation,  nearly 
all  of  it  occurring  in  the  spleen,  liver,  and  lungs, 
and  it  is  in  the  collecting  of  the  leucocytes,  especially 
of  the  polynuclear,  in  these  situations  that  in  a  great 
part  accounts  for  the  leucopenia  in  the  peripheral 
circulation  after  injection  of  certain  micro-organisms. 
On  the  other  hand,  Wright  and  Douglas  found  that 
the  opsonin  content  of  citrated  plasma  was  the 
same  as  the  corresponding  serum.  I  think  myself 
that  it  is  probable  that  the  immune-body  and 
antitoxin  circulate  as  such  in  the  plasma,  but  that 
the  complement  and  heat-labile  opsonin  is  cast  out 
by  the  tissue  cells  at  need. 


CHAPTER  IV. 

AGGLUTINATION,  PRECIPITATION,  REACTIONS. 

We  have  still  to  consider  two  substances  occurring 
in  serum  of  infected  or  immunised  animals,  viz., 
agglutinins  and  precipitins,  whose  role  in  immunity 
we  do  not  know.  Indeed,  it  is  quite  likely  that  the 
phenomena  of  agglutination  and  precipitation  are 
functions  of  other  antibodies  of  a  complement-like 
nature  and  not  special  bodies  at  all.  The  phe- 
nomena are  very  useful  for  diagnostic  purposes. 
We  will  then  discuss  briefly  aggressins  and  then  pass 
on  to  consider  intravital  '  reactions.' 

Agglutinins. — If  the  serum  of  a  patient  suffering 
or  recovering  from  typhoid  fever,  or  that  of  an 
animal  or  man  who  has  been  inoculated  with 
typhoid  vaccine,  be  mixed  with  a  suspension  of  the 
typhoid  bacillus,  the  bacilli  are  observed  under  the 
microscope  to  approach  one  another  and  to  become 
attached  by  their  flagellae ;  they  whirl  round  and 
round  as  if  making  frantic  efforts  to  free  themselves 
and  then  gradually  become  quiescent  as  if  from 
exhaustion  ;  more  and  more  microbes  become  at- 
tached until  all  the  microbes  are  united  in  clumps 
and  are  motionless.  In  the  test-tube  the  uniform 
opalescence  of  the  bacillary  suspension  is  observed 
to  become  more  granular,  then  flocculent ;  then  the 

42 


Agglutination,  Precipitation,  Reactions. 


flocculi  adhere  into  masses  which  sink  to  the  bottom 
of  the  tube.  The  phenomenon  which  is  known  as 
the  Widal  reaction  can  also  be  very  well  seen  by 
making  the  dilutions  in  capillary  tubes. 

This  agglutination  is  brought  about  by  comple- 
ment-like substances  known  as  agglutinins,  which 
are  inactivated  by  heating  to  70 — 75  deg.  C,  and 
by  the  same  physical  and  chemical  means  as  com- 
plement being  converted  into  agglutinoids  which 
have  the  haptophore  group  intact. 

They  are  produced  by  infection  or  inoculation 
with  certain  particulate  substances  of  cellular 
origin,  or  by  cells  themselves,  such  as  microbes,  red 
and  white  corpuscles  and  other  cells. 

Agglutinoids  have  the  power  of  preventing 
agglutination,  owing,  apparently,  to  their  more 
active  combining  power  with  the  antigen,  and  of 
thus  shutting  out  agglutinins.  Agglutinins  can 
combine  at  0  deg.  C,  but  agglutination  does  not 
take  place  until  a  temperature  approaching  the 
body  temperature  is  reached. 

It  has  been  found  in  doing  the  Widal  reaction, 
for  instance,  that  agglutination  may  take  place 
when  the  serum  is  diluted  to  i  in  10,  and  so  on, 
when  diluted  up  to,  say,  i  in  100,  and  then  there  is 
a  series  of  dilutions  in  which  no  agglutination  takes 
place,  but  when  a  higher  dilution,  say  i  in  10,000 
is  reached  agglutination  again  takes  place.  The 
explanation  of  these  '  zones  of  inhibition  '  I  shall  not 
go  into  here,  but  I  mention  it  as  it  is  of  practical 
importance. 

Agglutinins    are    not    absolutely   specific.  A 
43 


Therapeutic  Immunisation. 


typhoid  serum  may  agglutinate  the  Bacillus  coli 
or  the  paratyphoid  bacillus,  but  it  only  does  so  in 
low  dilution ;  for  instance,  it  may  clump  the  typhoid 
bacillus  in  a  dilution  of  i  in  500  or  in  i  in  1,000, 
while  it  will  only  clump  the  colon  bacillus  in  i  in  10. 
These  are  known  as  '  group  reactions,'  the  microbes, 
mentioned  above,  belonging  to  the  typhoid-coli 
group  of  microbes. 

Agglutinins  are  also  found  in  the  serum  of  indi- 
viduals who  have  not  been  inoculated  and  have 
not  suffered  from  the  disease  ;  they  have  been  found 
in  the  blood  serum  of  infants.  Probably  they  are 
produced  by  autoinoculation — for  instance,  from  the 
intestine.  Horse  serum  frequently  clumps  the 
typhoid-coli  group  and  also  the  tetanus  bacillus, 
and  these  are  common  inhabitants  of  the  intestines 
of  horses  and  cattle. 

Each  injection  of  the  antigen  is  followed  by  a 
negative  phase,  and  this  is  succeeded  by  a  positive 
phase.  A  marked  drop  in  the  amount  of  agglutinin 
has  been  observed  to  accompany  a  relapse  in 
typhoid  fever. 

If  the  bacilli  are  filtered  off  from  an  old  typhoid 
culture  and  injected  into  an  animal  it  will  produce 
agglutinin,  and  if  this  filtrate  be  mixed  with  its 
antiserum  a  flocculent  precipitate  will  form.  This 
is  known  as  Kraus'  phenomenon.  Agglutinins  are 
often  used  as  a  test  for  the  degree  of  immunity,  and 
are  sometimes  extremely  useful  for  this  purpose. 

Precipitins  are  produced  by  inoculation  of  an 
animal  with  solutions  of  proteins.  If  the  serum  of 
an  animal  thus  immunised  and  a  solution  of  the 


44 


Agglutination,  Precipitation,  Reactions. 


antigen  be  mixed  together  a  precipitate  forms. 
One  would  naturally  think  that  an  antibody  was 
formed  which  caused  the  precipitation  of  the 
antigen-protein,  but  this  is  not  the  case,  for  it  has 
been  clearly  shown  that  the  precipitate  is  so  great 
that  it  could  not  possibly  be  formed  from  the  antigen- 
protein  present.  To  take  an  example.  One  milli- 
gramme of  egg-white  interacting  with  fifty- two  cubic 
centimetres  of  its  antiserum  yielded  a  precipitate 
weighing  25-9  milligrammes.  The  supernatant  fluid 
still  contained  antigen  in  solution.  It  is  clear  that 
25  milligrammes  of  precipitate  could  not  have  been 
formed  from  i  milligramme  of  antigen-protein.  The 
bulk  of  the  precipitate  is  added  to  by  adsorption  to 
it  of  all  complement-like  substances  present  in  the 
serum.  It  appears  that  the  same  antigen  may  act 
over  and  over  again  with  fresh  additions  of  antiserum, 
and  seems  to  suffer  little  sensible  diminution. 

It  will  not  be  necessary  for  us  to  go  further  into 
the  theory  of  the  phenomenon.  It  is  used  as  a  test 
for  the  identification  of  an  unknown  blood,  such 
as  found  in  a  blood-stain.  Some  remarkable 
diagnoses  have  been  made  by  this  means. 

The  reaction  takes  place  best  at  body  tempera- 
ture, and  precipitation  does  not  occur  if  the  anti- 
serum is  inactivated  by  heat.  It  is  found  also  that 
if  antigen  and  heated  antiserum  are  mixed  together, 
incubated  and  then  unheated  antiserum  added,  no 
precipitation  takes  place. 

It  has  been  shown  that,  provided  the  antiserum 
is  strong  enough,  it  will  react  with  protein  taken 
from  alUed  species,  but  it  acts  far  more  strongly 

45 


Therapeutic  Immunisation. 


and  in  much  higher  dilution  with  the  antigen  pro- 
ducing it.  An  antiserum  to  human  blood  serum 
acts  very  strongly  with  it,  less  strongly  with  the 
blood  serum  of  monkeys  and  much  less  strongly 
with  that  of  other  mammals,  and  not  at  all  with 
that  of  birds,  reptiles  or  fishes. 

The  test  is  given  with  very  dilute  solutions  of 
antigen;  a  solution  containing  i — 100,000  of  egg 
albumen  has  been  found  to  react,  as  has  i — 50,000 
dilution  of  human  serum.  If  a  blood-stain  has  to  be 
tested,  it  is  first  broken  up  and  dissolved  in  normal 
saline  solution  and  then  carefully  titrated  with 
various  antisera,  such  as  human,  bovine,  avian,  etc. 
A  strong  precipitate  indicates  the  identity  of  the 
blood. 

As  mentioned  above,  when  a  precipitate  forms 
complement  is  adsorbed  or  fixed  to  it,  so  that  if 
sensitised  red  corpuscles  are  subsequently  added 
to  it  no  haemolysis  takes  place.  The  presence  of  a 
precipitate  which  may  be  invisible  to  the  naked 
eye  can  in  this  way  be  detected. 

Aggressins. — It  will  only  be  necessary  for  me  to 
briefly  refer  to  substances  which  were  supposed  to 
act  on  phagocytic  leucocytes  in  a  negatively 
chemiotactic  manner ;  to  these  substances  Bail 
gave  the  name  of  '  aggressins,'  and  built  up  a  theory 
of  immunity  on  his  experiments.  One  would  hardly 
expect  that  microbes  would  go  to  the  trouble  of 
making  a  special  substance  to  act  on  leucocytes,  when 
they  already  produced  substances,  viz.,  toxins,  which 
must  have  already  an  aggressive  effect,  and  it 
appears  estabUshed  that  Bail's  aggressins  are  really 

46 


Agglutination,  Precipitation,  Reactions. 


either  exo-  or  endo-toxins  and  that  there  is  no 
evidence  of  a  negatively  chemiot actio  effect. 

I  have  now  described  all  the  immune  substances 
that  it  is  necessary  to  consider,  and  will  conclude 
this  chapter  by  describing  certain  intravital  *  re- 
actions '  which  are  of  the  utmost  importance. 

They  all  of  them  depend  on  the  presence  in  the 
blood  and  tissue  fluids  of  antibodies  to  the  antigen 
used  to  produce  them.  They  are  all  major  or  minor 
manifestations  of  a  condition  known  as  anaphylaxis, 
a  term  which  signifies  the  opposite  of  immunity, 
and  was  the  name  given  by  Richet  to  an  illness, 
often  fatal,  produced  in  rabbits  and  guinea-pigs  by 
an  injection  of  protein  material  from  sea-anemones, 
followed  by  another  injection  of  the  same  protein 
at  a  certain  interval.  The  first  or  sensitising  dose 
was  perfectly  innocuous ;  the  second  or  assaulting 
dose,  often  a  smaller  one,  sometimes  caused  death 
in  a  few  minutes.  Richet's  explanation  is  that  the 
first  dose  causes  the  formation  of  an  antibody, 
and  this  reacts  with  the  fresh  antigen  when  injected 
to  form  a  toxin  (apotoxin)  which  produced  the 
symptoms.  This  explanation  is  interesting,  for  the 
symptoms  of  anaphylaxis  are  very  like  those  of 
peptone-poisoning,  and  it  may  be  that  the  protein 
is  broken  down  by  the  action  of  complement  and 
immune-body  (ferment  and  coferment)  with  the 
formation  of  a  peptone-like  body. 

Since  the  symptoms  of  anaphylaxis  in  a  rabbit  are 
more  like  those  in  a  human  being  than  those  in  a 
guinea-pig,  they  will  be  described  somewhat  in 
detail. 


47 


Therapeutic  Immunisation. 


The  rabbit  may  be  sensitised  by  giving  5  c.c.  of 
the  foreign  protein  {e.g.,  blood  serum)  per  kilo  of  its 
body-weight.  When  a  well-marked  amount  of  anti- 
bodies are  present,  viz.,  immune-body  and  pre- 
cipitin, a  small  dose,  say  0  3  c.c,  of  the  antigen  is 
given.  It  has  been  found  that  the  severity  of  the 
symptoms  is  proportional  to  the  amount  of  antibody 
present. 

Sometimes  within  fifteen  seconds  after  starting 
to  give  the  assaulting  dose  intravenously  the  ears 
are  seen  to  flush  and  the  veins  to  pulsate,  the 
breathing  is  shortened  and  there  are  periods  of 
apnoea :  this  phase  lasts  from  two  seconds  to  one 
minute  and  is  followed  by  marked  anaemia  and 
cyanosis  of  the  ears.  It  is  most  difficult  to  get 
the  veins  to  bleed,  and  the  blood  that  does  flow  has 
a  prolonged  clotting  time,  the  respirations  become 
panting  and  heart-beats  extremely  rapid.  The 
animal  is  restless  and  appears  anxious.  In  two  or 
three  minutes  muscular  weakness  appears,  the 
animal  lies  prostrate  and  unconscious,  with  flaccid 
muscles  and  distended  abdomen  with  relaxed 
muscular  walls.   Urine  and  faeces  are  discharged. 

In  five  to  ten  minutes  this  stage  of  depression  is 
at  its  maximum,  and  rapid  death  may  occur,  pre- 
ceded by  convulsions.  The  heart  keeps  beating  for 
several  minutes  after  the  loss  of  the  corneal  reflex 
and  the  cessation  of  respiration. 

In  non-fatal  cases  {e.g.,  when  little  antibody  is 
present)  there  may  be  only  transitory  anaemia  of  the 
ears  and  dyspnoea,  the  animal  rapidly  recovering ; 
or  the  animal  may  be  unconscious  for  half  an  hour 

48 


Agglutination,  Precipitation,  Reactions. 


and  recover  in  a  couple  of  hours.  If  it  does  recover 
it  is  immune  for  one  or  more  days,  and  is  then  as 
susceptible  as  ever. 

If  the  injection  is  given  subcutaneously,  there  is 
severe  oedema  around  the  site  of  the  injection. 

During  the  illness  there  is  a  marked  leucopenia  in 
the  peripheral  circulation.  This  is  not  due  to  a 
sudden  destruction  of  the  leucocytes,  but  to  the  fact 
that  there  is  an  enormous  concentration  of  them  in 
the  capillaries  of  the  lungs,  liver  and  spleen,  and 
also  to  the  engorgement  of  the  portal  veins.  There 
is  marked  spasm  of  the  bronchioles. 

The  clotting  time  of  the  blood  in  the  veins  is 
prolonged  and  there  is  a  very  marked  diminution  of 
complement-like  substances  in  the  blood. 

As  I  have  already  said,  it  is  owing  to  the  develop- 
ment of  this  hypersensitiveness  that  treatment  of 
chronic  diseases  with  sera  given  subcutaneously  or 
intravenously  is  unsuitable.  I  myself  have  had  a 
very  unpleasant  experience  in  treating  a  case  of 
tuberculosis  of  the  lungs  with  an  anti-tubercular 
serimi.  The  patient  had  had  a  number  of  intra- 
muscular injections.  After  the  tenth  she  got  very 
ill ;  when  I  saw  her  about  six  hours  after  she  had  a 
giant  oedema  from  her  hip,  where  the  injection  was 
given,  to  her  shoulder,  her  pulse  was  fast  and 
thready,  she  was  cyanosed  and  had  dyspnoea,  this 
state  of  collapse  gradually  passed  off  and  the 
oedema  gradually  disappeared.  Two  other  cases  of 
severe  anaphylaxis  occurred  in  my  practice;  the 
serum  was  being  given  intravenously  for  the  treat- 
ment of  pulmonary  haemorrhage.  In  neither  case  had 

49  4 


Therapeutic  Immunisation. 


the  patient  any  knowledge  of  a  previous  injection 
of  serum.  Before  0*25  c.c.  had  been  given  the 
patients  began  to  sniff  owing  to  nasal  irritation 
and  within  a  few  seconds  were  in  a  state  of  collapse 
with  dilated  pupils,  thready  feeble  pulse  and  severe 
dyspnoea.  The  first  case  developed  congestion  of  the 
lungs  from  which  he  died  in  ten  days.  In  the  second 
the  symptoms  were  rapidly  relieved  by  two  0*5  c.c. 
doses  of  pituitrin  given  subcutaneously.  Pituitrin 
also  rapidly  relieves  serum  rashes. 

These  cases  were  probably  due  to  partial  digestion 
of  the  proteins  by  the  tryptoid  ferments  which  were 
allowed  to  act  by  the  destruction  or  removal  of 
antitrypsin  by  some  method  not  yet  explained. 
Another  interesting  case  of  anaphylaxis  was  related 
to  me  by  a  colleague.  A  lady  who  had  had  a  sub- 
cutaneous injection  of  anti-diphtheritic  serum  for 
prophylactic  purposes  noticed  that  a  lump  remained 
at  the  site  of  injection.  About  a  week  after  she 
struck  her  hip  at  the  site  of  inoculation  against  a 
chair  and  the  lump  disappeared.  A  short  time 
after  she  was  cyanosed  and  collapsed  with  severe 
dyspnoea,  in  a  typical  and  alarming  state  of  anaphy- 
laxis. Such  an  accident  could  not  have  occurred  if 
the  serum  had  been  given  intravenously,  or  if  toxin 
had  been  used  (see  p.  105).  Anaphylaxis  sometimes 
occurs  in  the  use  of  vaccines ;  this  is  especially  the 
case  with  those  which  most  easily  undergo  lysis, 
such  as  typhoid  vaccine.  I  have  never  found  it  of 
importance  in  practice,  but  it  has  been  produced 
experimentally  in  animals. 

There  are  many  explanations  given  for  the  condi- 

50 


Agglutination,  Precipitation,  Reactions. 


tion,  e.g.,  severe  shock  to  the  central  nervous  system 
— it  is  said  not  to  occur  if  the  animal  is  anaesthetised 
with  ether  before  giving  the  assaulting  dose. 
Liberation  of  a  toxin — the  condition  is  very  Hke 
that  seen  in  peptone  poisoning.  Formation  of  a 
precipitate.  Fixation  of  complement  throughout 
the  system  by  the  sensitised  antigen,  and  so  on. 
All  the  symptoms  could  be  explained  by  any  of 
these  hypotheses.  Anything  that  would  affect 
nutrition  would  be  felt  first,  or  rather  first  exhibited, 
by  the  nervous  system,  and  fixation  of  complement- 
like ferments,  which  are  essential  to  cellular- 
nutrition,  must,  however  slightly,  affect  such  highly 
organised  and  sensitive  cells.  Moreover,  this  fixation 
can  take  place  either  to  sensitised  antigen  or  to  a 
precipitate.  In  the  case  of  an  antigen  such  as 
typhoid  vaccine,  whose  lysis  would  liberate  a  toxin, 
an  additional  poisonous  factor  is  added. 

The  literature  and  experiments  on  this  subject 
are  enormous.  But  I  think  I  have  now  mentioned 
as  much  of  the  subject  as  is  necessary  for  practical 
purposes. 

Most  of  the  skin  reactions  for  diagnostic  purposes 
are  '  local '  manifestations  of  anaphylaxis ;  they  have 
been  chiefly  used  for  the  diagnosis  of  tubercular 
disease.  The  local  reaction  may  be  due  to  fixation 
of  complement  affecting  the  nutrition  of  the  cells 
locally  or  to  lysis  of  the  microbial  protein  liberating 
endotoxin.  Anyhow,  it  does  not  take  place  unless 
antibodies  to  the  particular  antigen  are  present. 

Calmette's  conjunctival  reaction  occurs  if  a  drop 
of  glycerine-free  old  tubercuhn  (AT)  (see  p.  216) 

5^ 


Therapeutic  Immunisation. 


is  dropped  into  the  conjunctival  sac  of  a  tubercular 
patient.  There  is  redness  and  swelling  of  the 
caruncle  and  mucous  membrane,  coming  on 
generally  within  twelve  hours  when  the  reaction  is 
positive.  If  it  fails  the  first  time,  one  is  directed  to 
do  it  again  in  the  other  eye.  I  do  not  think  this  is 
logical,  as  the  first  dose  might  have  sensitised  the 
patient.  The  test  has  been  given  up  to  a  large 
extent  owing  to  the  fact  that  it  has  been  done  on 
inflamed  conjunctivae  with,  in  some  cases,  subsequent 
sloughing  of  the  cornea  necessitating  removal  of 
the  eye. 

Von  Pirquet's  test  is  done  by  rubbing  old  tuber- 
culin into  the  Malpighian  layers  of  the  epidermis 
after  rubbing  off  the  horny  layers.  A  positive 
reaction  is  indicated  by  an  area  of  swelling  of  the  skin 
with  a  brighter  red  colour  round  the  abrasion.  A 
control  mark  is  also  made  into  which  no  tubercuKn 
is  rubbed.  Some  use  a  series  of  dilutions  from,  say, 
10  per  cent,  to  lOO  per  cent.,  and  say  it  gives  them 
an  indication  of  the  amount  of  antibody  present. 
The  test  is  not  given  in  acute  miliary  tuberculosis 
nor  in  the  last  stages  of  the  disease ;  the  same  remark 
applies  to  all  these  tests. 

In  Moro's  test  the  tubercuUn  is  diluted  with  an 
ointment  and  is  rubbed  in ;  red  papules  indicate  a 
positive  reaction.  Another  method  is  to  make  a 
small  blister,  remove  the  raised  epidermis  and  apply 
the  tubercuhn  to  the  raw  surface. 

Yet  again,  it  has  been  injected  into  the  skin  with 
a  needle  and  syringe. 

Except  in  young  children  none  of  these  tests  are 
52 


Agglutination,  Precipitation,  Reactions. 


very  reliable.  Since  we  have  all  been  infected  with 
tuberculosis  on  reaching  adult  years,  a  healthy 
adult  without  antibodies  to  the  tubercle  bacillus 
must  be  a  curiosity.  As  a  rule  a  negative  reaction 
is  of  more  importance  than  a  positive  one.  A  col- 
league of  mine,  a  robust,  healthy  pathologist,  did 
Von  Pirquet's  reaction  on  himself  and  got  a  most 
violent  reaction. 

Similar  reactions  have  been  tried  for  the  diag- 
nosis of  other  diseases,  such  as  typhoid  ;  Widal  and 
other  such  reactions  are  far  more  satisfactory. 


53 


CHAPTER  V. 


THERAPEUTIC  IMMUNISATION. 

,  Having  now,  sufficiently  for  our  purpose,  con- 
sidered the  different  immunity  mechanisms,  we 
shall  in  this  chapter  consider  how  this  knowledge 
can  be  applied  to  the  prevention  and  treatment  of 
infections. 

Therapeutic  inoculation  falls,  naturally,  under  two 
heads,  viz.,  (i)  The  production  of  passive  immunity 
by  means  of  antibody-containing  sera  of  animals 
immunised  against  the  disease  and  (2)  the  induction 
of  active  immunity  by  inoculating  the  patient  with 
killed  suspensions  (vaccine)  of  the  microbe  itself 
more  or  less  modified. 

A  combination  of  the  two  processes  is  of  great 
advantage  in  certain  cases. 

The  production  of  passive  immunity  can  be  used 
both  for  treatment  and  prophylaxis.  Sera  con- 
taining antitoxin  for  the  toxin  of  the  diphtheria 
bacillus  and  of  the  tetanus  bacillus  are  used  for  both 
purposes,  and  these  sera  are  efficient. 

The  other  sera  in  use  are  bacteriolytic  or  bacteri- 
cidal and  are  usually  anti-endotoxic  as  well.  As  a 
whole  they  are  not  so  satisfactory  as  the  antitoxic 
sera,  but  brilKant  results  are  sometimes  obtained. 

For  prolonged  treatment  all  sera  have  the  dis- 

54 


Therapeutic  Immunisation. 


advantage  that  when  given  intravascularly  or 
subcutaneously  the  patient  often  becomes  hyper- 
sensitised  to  the  protein  contained  in  them,  with  the 
consequent  production  of  rashes  and  other  anaphy- 
lactic symptoms,  so  that  unless  given  via  a  mucous 
membrane  it  is  better  to  confine  their  use  to  acute 
infections.  They  are  to  be  obtained  commercially 
for  the  treatment  of  many  of  the  common  patho- 
genic micro-organisms,  such  as  the  staphylococcus, 
various  strains  of  the  streptococcus,  pneumococcus 
typhoid  bacillus,  and  the  meningococcus.  They 
are  produced,  as  a  rule,  by  inoculating  the  animal 
at  first  with  small  doses  of  the  killed  microbe  ; 
these  doses  are  gradually  increased  until  the  animal 
can  eventually  stand  a  large  dose  of  the  live  microbe. 

The  efficiency  of  these  sera  depends  on  the  amount 
of  anti-endotoxin  present,  for  a  dose  of  serum  con- 
taining only  bacteriolytic  immune-body  may  in 
certain  conditions,  e.g.,  typhoid  fever,  do  harm, 
owing  to  solution  of  bacilli  and  a  liberation  of  a 
large  amount  of  endotoxin,  which  would  further 
poison  the  patient. 

Active  Immunity. — Active  immunisation  for  pro- 
phylaxis and  treatment  is  becoming  more  and  more 
extensively  used. 

The  production  of  active  immunity  for  prophy- 
lactic purposes  appears  at  once  to  be  a  logical  and 
useful  procedure.  Such  vaccines  are  used  in  the 
prophylaxis  against  various  diseases,  that  is,  active 
immunity  is  produced  in  the  person  who  may  be 
exposed  to  the  disease ;  one,  two  or  more  increasing 
doses  are  given  which  stimulate  the  antibody  power 

55 


Therapeutic  Immunisation. 


of  the  subject  for  a  certain  time  and  may  tide 
him  through  an  epidemic.  This  method  is  now 
extensively  used  against  the  typhoid  bacillus,  the 
bacillus  paratyphosus  A  and  B,  the  various  dysentery 
bacilli  and  the  bacilli  of  plague  and  cholera,  and  other 
epidemic  infections,  and  I  use  it  against  the  tubercle 
bacillus. 

On  the  other  hand,  the  reasons  for  the  inoculation 
of  a  patient,  who  is  already  suffering  from  an 
infection,  with  more  of  the  virus  of  that  infection  are 
not  so  obvious  and  the  procedure  puzzles  the  minds  of 
many.  It  seems  to  me  that  it  is  best  to  look  at  the 
matter  in  the  following  way,  viz.,  that  in  the  majority 
of  infections  not  all  the  tissues  of  the  body  which  are 
capable  of  producing  antibodies  are  producing  them, 
and  that  by  inoculation  these  tissues  are  made  to 
take  their  proper  share  in  the  fight. 

Even  in  acute  septicaemic  infections,  such  as 
typhoid  fever,  it  has  been  conclusively  proved  that 
the  subcutaneous  tissues  are  capable  of  stimulation. 
No  doubt  the  actively  phagocytic  endothelial  cells 
of  the  blood-vessels,  which  control  the  passage  of 
substances  into  the  tissues,  play  an  active  part  in 
the  protection  of  the  tissues  from  circulating  toxins 
and  microbes.  The  whole  question  of  recovery  or 
not  in  these  acute  generalised  infections  depends,  I 
think,  on  whether  these  tissues  have  been  sufficiently 
protected  to  be  capable  of  further  response.  If  they 
are  not  or  are  only  capable  of  very  little,  then  the 
only  hope  for  the  patient  is  the  use  of  antibodies 
produced  by  another  animal,  or  perhaps  the  use 
of  specific  antitoxic  or  germicidal  drugs,  such  as 

56 


Therapeutic  Immunisation. 


iodine  or  sulphur.  It  thus  appears  that  the  prog- 
nosis in  acute  septicaemic  infections  depends  on  the 
endotheUal  cells.  When  the  infection  is  very 
virulent  their  resistance  is  destroyed ;  they  are 
broken  down  with  the  appearances  of  haemorrhages 
into  the  tissues.  These  haemorrhagic  forms  of  acute 
infection  are  almost  invariably  rapidly  fatal,  for 
instance,  black  small-pox,  and  the  like. 

In  acute  cases  the  initial  dose  must  be  small,  as  a 
rule,  so  that  little  or  no  free  toxin  must  get  into 
circulation  and  so  produce  a  negative  phase. 

When  the  infection  is  strictly  localised  the 
rationale  is  not  so  difficult  to  understand,  for  the 
fact  that  it  is  localised  presupposes  a  certain  amount 
of  resistance  on  the  part  of  the  patient's  organism 
and  of  the  tissue  in  which  the  infection  is.  The 
disease  is  more  or  less  shut  off  by  granulation  tissue 
and  the  other  processes  of  inflammation  which 
prevent  to  a  greater  or  less  extent  the  escape  of 
microbes,  their  toxins  and  the  products  of  the  tissues 
broken  down  by  their  action,  into  the  general  cir- 
culation, but  are  not  quite  capable  of  absolutely 
destroying  the  microbes.  The  leucocytes  that  do 
attack  them  are  rapidly  killed,  for  while  they  may 
be  able  to  ingest  the  microbe  which  has  been  pre- 
pared by  the  normal  opsonising  action  of  comple- 
ment, yet  owing  to  the  absence  of  specific  antibodies 
they  are  not  able  to  digest  them  and  are  thus  killed 
and  form  pus,  the  fluid  part  of  which  is  found  very 
poor  in  antibodies.  It  is  difficult  for  fresh  anti- 
bodies to  get  into  an  abscess  cavity,  owing  to  the  back 
pressure  of  the  increasing  amount  of  fluid  produced 

57 


Therapeutic  Immunisation. 


by  increasing  liquefaction  of  the  tissues  by  ferments. 
So  that  in  treating  a  locaHsed  infection,  if  an  abscess 
is  present  it  must  be  evacuated  so  that  the  effete 
fluid,  in  which  the  antibodies  have  been  used  up 
and  which  contains  tryptoid  ferments  from  the  killed 
leucocytes,  may  be  got  rid  of  and  fresh  antibody- 
containing  serum  allowed  to  flush  the  infected  area. 

It  is  necessary  to  get  as  clear  a  view  as  we  can  of 
what  takes  place  in  the  subcutaneous  tissues,  at  the 
site  of  injection,  in  the  organism  as  a  whole,  and  in 
the  infected  tissues. 

The  phenomena  that  take  place  are  known  as 
reactions  and  are  called  '  local,'  '  general '  and 
'  focal,'  according  as  they  occur  at  the  site  of  injec- 
tion, in  the  whole  system,  and  at  the  site  of  infection. 

Any  or  all  of  these  may  be  absent  or  so  slight  as 
not  to  be  apparent. 

When  the  dose  is  moderate  the  local  reaction  is 
often  clinically  absent  or  merely  amounts  to  a  slight 
tenderness,  sometimes  with  a  little  redness  or 
swelling.  The  changes  in  the  subcutaneous  tissue 
are  those  of  the  early  stages  of  inflammation,  viz., 
increased  blood  supply  and  oedema  never  going  on 
to  formation  of  granulation  tissue  or  suppuration. 
Since  there  is  practically  always  present  a  certain 
amount  of  specific  immune-body  (coferment)  for 
all  the  common  micro-organisms,  especially  if  the 
patient  is  already  infected,  the  micro-organisms 
probably  undergo  lysis,  either  in  the  subcutaneous 
tissues  or  in  the  lymphatic  system,  at  any  rate  to  a 
certain  extent,  with  the  liberation  of  their  endotoxin. 

If  the  dose  is  very  minute  it  is  likely  that  little  or 

58 


Therapeutic  Immunisation. 


none  of  the  bacterial  protein  and  endotoxin  gets  into 
the  general  circulation,  the  protein  being  absorbed 
and  digested  and  anti-endotoxin  being  produced,  but 
in  greater  quantity  than  is  necessary  to  antagonise 
the  amount  of  antigen  injected,  so  that  this  sub- 
stance is  poured  into  the  general  circulation. 

If  the  dose  is  larger  bacterial  protein  and  endo- 
toxin escape  into  the  circulation  with  the  production 
of  a  general  reaction. 

The  symptoms  of  a  general  reaction  vary  in 
degree  from  a  transitory  feeling  of  tiredness  to  well- 
marked  malaise,  headache,  fever,  pains  in  joints, 
and  rapid  pulse.  This  general  reaction  passes  off 
after  a  longer  or  shorter  time  and  is  perhaps  followed 
by  an  increased  feeling  of  well-being,  if  the  dose  has 
not  been  too  great. 

These  symptoms  are  accompanied  by  changes  in 
the  leucocyte  and  ferment  content  of  the  blood  in 
the  peripheral  circulation. 

The  injection  of  a  moderate  dose  is  followed  by  a 
drop,  or  'negative  phase,'  in  both  the  number  of 
leucocytes  and  in  the  amount  of  complement-like 
substances  in  the  peripheral  circulation.  This  is 
followed  by  a  positive  phase,  in  which  all  are  in- 
creased ;  this  increase  lasts  a  longer  or  shorter  time, 
and  then  returns  to  normal.  There  is  no  exact 
relation  between  the  number  of  leucocytes  present 
and  the  amount  of  complement. 

The  fluctuations  in  the  amount  of  heat- labile 
opsonin  has  been  worked  out  by  Wright  and  others, 
by  means  of  the  '  opsonic  index,'  which,  as  we  have 
seen,  is  obtained  by  comparing  the  average  number 

59 


Therapeutic  Immunisation. 


of  microbes  taken  up  by  polynuclear  leucocytes  in 
a  mixture  containing  washed  leucocytes,  patient's 
serum  and  microbes,  with  the  average  number  taken 
up  in  a  preparation  containing  standard  serum.  It 
has  been  found  that  by  increasing  the  dose  during 
a  positive  phase  it  is  possible  to  increase  the  opsonic 
index  to  several  times  the  normal,  and  in  Wright's 
method  of  inoculation,  the  ideal  is  to  attain  a  dose 
of  vaccine  which  will  keep  the  patient's  opsonic 
index  as  high  as  it  will  go  until  the  patient  is  well. 
In  many  cases  this  plan  succeeds,  in  other  cases  it 
is  partially  successful,  while  in  others  it  fails.  I 
think  that  many  of  these  last  two  classes  can  be 
made  successful  if  another  plan  of  inoculation  is 
adopted  and  it  will  be  well  to  criticise  briefly  the 
opsonic  index  plan  of  treatment. 

The  opsonic  index  has  been  attacked  as  being 
uncertain  and  unreliable  in  its  results.  I  think  that 
done  by  the  same  hands  in  the  same  way  it  gives 
reliable  results.  But  it  has  been  found  that  using 
the  technique  of  Wright  and  Douglas  it  is  only 
possible  to  force  it  up  to  a  certain  height,  any  further 
increase  of  dose  not  affecting  it.*  A  comparatively 
small  dose  will  effect  this,  a  dose  which  is  generally 
too  small  to  induce  sufficient  specific  antibodies  to 
cure  the  patient  in  all  but  very  recent  infections. 
And  yet  we  know  that,  by  steadily  increasing  the 
dose,  more  and  more  specific  antibodies,  such  as 
immune-body  (coferment  for  the  digestion  of  the 
protein  of  the  microbe)  and  anti-endotoxin  appear, 

♦  To  get  a  true  measure  of  the  heat-labile  opsonin  a  dilution 
method  must  be  used. 

60 


Therapeutic  Immunisation. 


and  I  have  already  shown  that  these  increase  phago- 
cytosis of  microbes  and  their  intracellular  digestion. 
One  cannot  say  in  any  given  case  the  dose  which 
will  have  to  be  attained  before  the  patient  is  well. 

For  diagnosis  a  high,  low,  or  fluctuating  opsonic 
index  is  sometimes  valuable. 

For  spacing  doses,  if  one  was  in  doubt  it  may  also 
be  valuable,  for  it  is  better  to  give  the  injection  when 
there  is  plenty  of  complement. 

But  as  a  guide  to  the  amount  of  the  dose  it  is 
unsuitable,  for  it  does  not  indicate  the  amount  of 
specific  antibodies  present. 

As  a  rule,  the  more  recent  and  unlocalised  the 
infection  the  smaller  is  the  dose  that  need  be 
attained.  In  the  more  chronic  and  localised,  one 
may  have  to  attain  very  large  doses.  For  instance, 
I  have  had  to  work  up  to  30,000  million  in  a  case  of 
chronic  staphylococcal  infection. 

Focal  reactions  are  produced  at  the  site  of  infec- 
tion after  the  injection  of  a  vaccine. 

Some  unaltered  virus  reaches  it  through  the 
circulation  and  increases  the  poisoning  of  the  tissue 
cells  at  the  part  and  the  virulence  of  the  microbes 
present  and  so  leads  to  increased  inflammation.  If 
the  dose  has  been  properly  chosen,  this  is  followed 
by  a  subsidence  of  the  symptoms,  since  the  general 
positive  phase  has  occurred  and  the  poisoned  part 
is  flooded  by  a  large  amount  of  new  antibodies. 
The  increased  inflammation  may  be  so  slight  that 
it  does  not  give  rise  to  symptoms,  only  the  decrease 
of  these  being  noticeable.  Focal  reactions  are  thus 
most  useful  in  the  cure  of  the  condition. 

61 


Therapeutic  Immunisation. 


It  is  by  the  extent  of  the  local,  general  and  focal 
reactions,  especially  the  latter  two,  that  we  judge 
the  spacing  and  amount  of  our  doses. 

I  will  here  give  three  examples  of  types  of  cases 
to  illustrate  the  above  considerations. 

First,  the  acute,  in  which  there  is  a  general  septi- 
caemia. In  this  case  one's  ideal  is  to  make  a  certain 
amount  of  antibodies  and  to  give  such  doses  as  will 
effect  this,  without  any  free  toxin  getting  into  the 
blood.  The  doses  must  then,  as  a  rule,  be  small. 
The  effect  of  these  injections  is  often  magical. 
Whenever  possible  it  is  well  to  give  a  dose  of 
appropriate  antiserum,  in  order  to  produce  a  mixed 
immunity,  viz.,  passive  and  active. 

The  general  rules  for  the  spacing  of  doses  in  these 
cases  is  as  follows  : — 

If  the  temperature  falls  at  once  after  a  dose, 
give  the  next  dose  when  it  begins  to  rise  again.  If 
there  is  no  effect  on  pulse  and  temperature,  give  the 
next  dose  in  twenty-four  hours. 

If  the  temperature  and  pulse  rise,  one  must  wait 
until  the  reaction  is  over,  that  is,  until  the  tempera- 
ture and  pulse  fall  and  begin  to  rise  again  before 
giving  the  next  dose,  which  should  be  a  repetition 
of  the  last  dose  if  the  reaction  is  severe.  Such 
reactions  can  be  controlled  by  the  injection  of  some 
form  of  iodine,  such  as  iodoform  or  Szendeffy's 
combination  of  iodine,  menthol  and  radium.  Iodine, 
as  we  have  seen,  is  an  antitoxin  of  the  best  kind. 

The  second  type  is  a  more  recent  and  localised, 
more  or  less  acute  condition,  such  as  an  acute 
conjunctivitis  produced,  for  instance,  by  the  pneumo- 

^2 


Therapeutic  Immunisation. 


coccus.  Such  a  case  might  be  expected  to  get  well 
by  regulating  the  size  of  the  doses  by  means  of  the 
opsonic  index.  Personally,  I  find  that  if  this  is 
done  a  fair  proportion  of  cases  will  relapse  ;  and 
I  therefore  prefer  to  follow  the  plan  of  steadily 
increasing  the  doses  until  the  patient  is  well  and 
then  giving  two  or  more  doses  of  the  series  in  order 
to  leave  a  margin  of  safety. 

The  last  type  is  a  chronic,  very  localised  infection 
such  as  chronic  eczema  or  acne.  A  very  large  dose 
may  have  to  be  reached  before  such  cases  are  cured. 

The  initial  dose  varies  (i)  with  the  microbe  used  ; 

(2)  with  the  general  condition  of  the  patient  ; 

(3)  with  the  age  ;  (4)  with  the  site  of  the  lesion. 

If  one  finds  that  after  the  first  dose  there  is  too 
violent  a  reaction  one  waits  until  the  reaction  has 
passed  and  then  gives,  perhaps,  the  same  dose  again, 
or  a  smaller  dose  and  works  up.  Some  patients  are 
very  sensitive  at  first,  and  the  dose  must  be  very 
slowly  increased.  Later,  as  they  gradually  make 
more  antibodies  the  doses  may  be  more  rapidly 
increased  in  size.  A  good  rule  about  spacing  the 
doses  is  not  to  give  the  next  one  until  three  clear 
days  after  all  signs  of  reaction,  local,  general  or 
focal,  have  disappeared. 

Children  will,  as  a  rule,  require  a  smaller  dose  to 
begin  with  and  elderly  people  also,  and  in  the  latter 
one  has  sometimes  to  be  cautious  about  increasing 
the  dose,  for  I  find  that  one  cannot  always  attain 
to  doses  that  one  can  in  the  case  of  younger  patients. 

I  make  it  a  rule  not  to  give  an  injection  during 
the  few  days  before  and  during  the  first  few  days  of 

63 


Therapeutic  Immunisation. 


menstruation;  reactions  are  likely  to  be  more  severe 
at  this  period. 

The  best  places  to  inoculate  are  the  dorsum  ihi, 
parts  below  the  clavicle  and  on  the  back  into  the 
loose  fold  of  skin  behind  the  axilla  and  between  the 
scapulas.  There  is  frequently  a  certain  amount  of 
local  tenderness  and  the  injections  should  be  given 
where  they  will  least  interfere  with  the  patient's 
movements.  I  have  a  distinct  preference  for  the 
dorsum  ihi,  the  chest  and  the  axillary  fold,  especially 
the  first.  I  think  the  arm  is  a  bad  place  ;  there  is 
not  much  subcutaneous  tissue  and  the  arm  is 
constantly  moved. 

One  must  also  be  careful  to  avoid  getting  the 
injection  beneath  the  aponeurosis  covering  the 
muscle ;  this  causes  considerable  pain  at  the  time  of 
injection  and  great  stiffness  for  some  days  after. 

And  lastly,  the  injection  must  not  be  given  so  that 
the  vaccine  will  pass  through  lymphatic  glands  that 
are  already  poisoned  by  the  infection,  e,g,,  if  the 
infection  is  on  the  leg,  do  not  give  the  injection  in 
the  gluteal  region  of  that  side.  If  the  infection  is  in 
the  chest,  give  it  in  the  gluteal  region.  If  the 
infection  is  in  the  abdomen,  inoculate  in  the  chest  or 
back.  It  is  better  also  to  change  the  site  of  injection 
each  time.  I  generally  alternate  the  sides,  giving  on 
one  side  one  injection  and  on  the  other  the  next. 

Let  us  always  keep  clearly  in  our  minds  the  anti- 
bodies that  one  desires  to  produce,  and  let  us  review 
them  again  briefly. 

They  are  : — 

Opsonins.     Heat  labile,  compound  and  heat 

64 


Therapeutic  Immunisation. 


stable.  Heat  labile  are  complement-like  and  feebly 
specific.  The  heat  stable  part  of  the  compound 
opsonin  is  absolutely  specific,  as  is  the  heat  stable 
opsonin,  which  I  beUeve  to  be  anti-endotoxin. 

Bacteriolytic  and  Bactericidal  Bodies. — 
These  consist  of  immune-body,  which  is  specific 
and  of  complement  which  is  non-  or  feebly  specific. 
This  substance  may  be  a  danger  if  given  in  serum 
in  certain  general  infections,  owing  to  the  liberation 
of  endotoxins,  if  anti-endotoxin  is  not  present  in 
sufficient  quantities.  The  compound  opsonin  and 
these  substances  are  probably  identical. 

Antitoxins.  —  If  sufficient  anti-exo  or  anti- 
endotoxins  are  present  in  the  body  for  any  given 
microbe,  that  microbe  cannot  possibly  live  in  the 
body. 

In  most  infections  all  three  processes  take  place, 
more  or  less,  leading,  as  we  have  seen,  to  efficient 
phagocytosis.  ;  while  in  a  few  cases,  such  as  that 
of  infection  by  the  cholera-vibrio,  the  immunity  is 
chiefly  bacteriolytic  and  antitoxic. 

In  acute  infections  it  is  generally  only  necessary 
to  temporarily  increase  the  heat-labile  opsonin 
and  produce  a  small  amount  of  specific  antibodies. 
In  chronic  infections  it  is  often  necessary  to  produce 
a  large  amount  of  specific  antibodies,  and  this  is 
attained  by  steadily  increasing  the  dose  of  vaccine 
until  sufficient  for  the  case  is  produced. 

We  see,  then,  that  in  order  to  succeed  in  curing 
one's  patient  the  patient's  tissues  must  be  capable 
of  reacting,  the  doses  of  vaccine  must  be  given  at 
proper  intervals,  which  are  determined  by  the 

65 


Therapeutic  Immunisation. 


quality  of  these  reactions,  and  a  sufficiency  of  specific 
antibodies  must  be  produced  in  the  patient. 

Besides  these  several  further  things  are  essential 
for  complete  success. 

(a)  The  antigen  (vaccine)  must  be  adequate — that 
is,  must  be  of  good  quality  and  must  contain 
all  the  microbes  causing  the  disease,  if  the 
infection  is  mixed  as  it  so  often  is.  We 
cannot  expect  to  produce  suitable  anti- 
bodies for  the  microbes  invading  the  patient 
if  the  antigen  given  does  not  contain 
identical  material,  e.g,,  protein  and  toxins. 
{b)  The  physiological  derangements  of  the  patient 
should  be  restored  as  far  as  possible  to 
normal  so  that  the  tissues  may  be  in  the 
best  possible  condition  for  producing  the 
antibodies  for  their  action  on  the  microbes 
by  the  various  phagocytic  cells. 
(c)  For  a  completely  ideal  result  the  infected  tissues 

must  be  capable  of  restoration  to  normal. 
We  have  already  seen  (Chapter  I.),  owing  to  the 
rapidity  with  which  microbes  reproduce  themselves, 
how  quickly  they  can  adapt  themselves  to  their 
environment  and  how  often  they  lose  their  virulence 
(capacity  for  breaking  down  living  tissues)  when 
leading  a  saprophytic  existence,  and  increase  it 
when  passed  through  a  series  of  susceptible  animals. 
The  fact  that  a  microbe  has  invaded  a  patient  and 
survived  shows  that  it  has  completely  adapted  itself 
to  that  particular  host,  which  means  that  its  fer- 
ments can  break  down  that  host's  tissues.  These 
ferments,  however,  might  be  quite  helpless  against 

66 


Therapeutic  Immunisation. 


the  tissues  of  another  host.  So  that  while  the  antigen 
may  contain  microbes  identical  with  the  microbes 
invading  a  patient  it  may  not  contain  the  qualities 
necessary  for  success  unless  it  is  isolated  from  the 
patient  himself. 

This  point  is  well  illustrated  by  the  meningococcus 
and  pneumococcus,  where  the  antiserum  produced 
by  one  strain  is  quite  helpless  against  the  bodies  and 
toxins  of  another  strain.  To  overcome  this  antisera 
are  produced  by  antigens  containing  microbes  from 
as  many  strains  as  possible  and  stock  vaccines 
contain  microbes  from  many  sources.  Stock 
vaccines  of  some  microbes,  e.g,,  staphylococci, 
the  typhoid  bacillus,  and  the  tubercle  bacillus,  can 
often  be  used  with  success,  provided  an  accurate 
diagnosis  of  the  invading  microbe  has  been  made, 
provided  they  are  made  from  recently  isolated 
microbes  on  suitable  media,  and  provided  a  suitable 
dosage  is  used. 

Too  often,  however,  they  are  made  from  old 
laboratory  strains,  are  spoiled  in  their  manufacture 
and  suitable  series  of  doses  are  not  obtainable 
commercially.  Moreover,  they  are  constantly  used 
without  any  bacteriological  diagnosis  having  been 
made. 

Furunculosis  is  not  always  produced  by  staphy- 
lococci. Acute  urethritis  is  not  always  caused  by 
the  gonococcus.  Further,  while  a  primary  infection 
is  caused  usually  by  a  single  infection,  very  con- 
stantly, as  we  shall  see  in  succeeding  chapters,  the 
tissues  whose  resistance  is  thus  lowered  become 
invaded  by  other  microbes,  so  that  the  infection  is  a 

67 


Therapeutic  Immunisation. 


mixed  one.  It  is  impossible  to  accurately  provide  for 
these  varying  secondary  invaders  in  a  stock  vaccine, 
and  yet  it  is  essential  for  success  that  the  vaccine 
should  contain  them.  Otherwise  the  case  may  be 
made  worse  instead  of  better  because  the  resistance 
of  the  infected  cells  is  lowered  during  the  negative 
phase  to  all  the  infecting  microbes,  and  if  this  is  not 
compensated  by  the  arrival  of  specific  antibodies 
for  a  particular  infecting  microbe  that  microbe  may 
be  left  with  increased  virulence  while  the  phagocytic 
powers  of  the  body-cells  for  that  microbe  are 
diminished. 

Microbes  being  so  rapidly  and  readily  influenced 
by  environment  it  is  most  important  that  they  should 
be  grown  on  a  medium  as  nearly  as  possible  like 
that  of  the  host.  This  is  best  attained  in  the  case  of 
human  cases  by  adding  fresh  human  blood  pre- 
ferably that  of  the  patient,  to  the  culture  medium 
in  the  proportion  of  about  i  c.c.  of  blood  to  lo  c.c. 
of  medium,  solid  or  liquid.  It  is  most  important 
also  that  the  medium  should  not  have  been  heated 
to  more  than  loo  deg.  C.  in  manufacture  in  order 
that  the  vitamines,  which  are  as  necessarj^  for  the 
welfare  of  the  microbe  as  for  higher  forms  of  Hfe, 
should  not  have  been  destroyed  and  that  it  should 
be  made  from  fresh  meat.  Media  made  on  these 
hues  will  grow  practically  all  pathogenic  microbes, 
even  the  most  difiicult,  such  as  the  meningococcus, 
so  that  a  causal  microbe  is  not  likely  to  be  missed 
owing  to  its  failure  to  grow. 

Stock  vaccines  have  been  prepared  in  several 
different  ways,  some  being  composed  of  suspensions 

68 


Therapeutic  Immunisation. 


of  living  microbes  modified  in  virulence  by  con- 
tinuous sub-culture,  growing  at  a  high  temperature 
or  other  way,  or  live  suspensions  sensitised  with 
immune-body  have  been  used,  as  have  dead  sensi- 
tised suspensions.  I  have  not  found  that  these 
sensitised  vaccines  give  any  better  results  than  the 
ordinary  killed  suspensions,  and  the  sensitisation 
greatly  complicates  the  manufacture  and  adds  to 
its  expense.  Live  vaccines  are  supposed  to  increase 
the  quality  of  the  immunity  produced.  The  evidence 
on  this  point  is  quite  inadequate  and  is  more  than 
counterbalanced  by  the  greatly  increased  risk. 
Suspensions  of  microbes  in  '5  per  cent,  phenol  in 
•9  per  cent,  sodium  chloride  recently  isolated  on 
media  manufactured  as  described  and  containing 
fresh  human  blood  have  given  in  my  hands  entirely 
satisfactory  results,  and  in  my  opinion  any  further 
complication  is  undesirable  and  unnecessary. 

It  is  of  the  greatest  importance  that  the  reaction 
of  the  blood  and  tissue  fluids  should  be  normal,  so 
that  the  processes  of  nutrition  may  proceed  effectively 
and  the  production  of  antibodies  and  their  action  be 
efficient.  Owing  to  the  over-production  of  acid 
products  of  metabolism  and  their  deficient  oxidation 
the  normal  mechanism  by  which  abnormal  concen- 
tration of  hydrogen  ions  in  the  system  is  corrected 
is  constantly  upset  in  disease.  This  is  best  combated 
by  giving  disodium  hydrogen  phosphate  or  sodium 
citrate.  Very  frequently,  too,  in  chronic  infections 
the  internal  secretions  of  various  glands  is  deficient 
as  well  as  the  various  hormones  acting  on  the  glands 
producing  the  exoferments  of  the  intestinal  tract. 

69 


Therapeutic  Immunisation. 


Opotherapy  is  exceedingly  useful  for  the  replacing 
or  substitution  of  these. 

It  is  generally  assumed  that  the  therapeutic 
immunisator  has  no  use  for  the  older  methods  of 
therapeutics,  mechanical,  pharmacological,  and  so  on. 
If  anyone  who  practises  the  former  methods  assumes 
such  an  attitude  he  will  frequently  severely  handicap 
himself  in  the  treatment  of  his  patient  and  is  just 
as  fooHsh  as  the  physician  who  takes  the  opposite 
point  of  view. 

While  it  is  impossible,  with  few  exceptions,  to 
effect  the  replacement  of  destroyed  tissues,  yet  con- 
stantly the  destruction  can  be  limited  to  such  an 
extent  that  the  tissues  destroyed  will  not  be  missed 
or,  at  any  rate,  can  be  done  without,  even  if  the 
patient  may  suffer  physiologically  for  the  rest  of  his 
life,  as  when  nerve  cells  are  destroyed. 

The  great  aim  of  medicine  must  be  to  prevent 
the  invasion  and  damage  of  vital  organs  by  microbes, 
an  ideal  the  methods  for  the  accomplishment  of 
which  will  be  especially  dealt  with  in  succeeding 
chapters. 


70 


CHAPTER  VI. 


ALIMENTARY  CANAL. 

There  is  no  need  to  labour  the  importance,  to  the 
well-being  of  the  individual,  of  keeping  the  gastroin- 
testinal in  good  working  order.  Owing  to  the 
constant  ingestion  of  food,  the  gastrointestinal  tract 
is  peculiarly  liable  to  infections  which  may  be  con- 
tained in  it  (the  food),  and  the  more  distant  parts  of 
it  can  be  infected  by  swallowing  of  pathogenic 
microbes,  when  these  are  causing  lesions  of  the 
mouth  and  respiratory  passages.  Further,  it  is  the 
home  of  certain  micro-organisms,  which  are  so  con- 
stantly present  as  to  be  considered  normal.  Such  are 
the  Bacillus  coli  communis,  streptococci,  and  certain 
anaerobic  bacilli.  We  know  that  microbes  are  con- 
stantly passing  through  the  intestinal  wall  into  the 
radicals  of  the  portal  veins  and  lymphatics,  being 
carried  through  by  leucocytes  which  are  carrying 
foodstuffs  in  ;  such  microbes  have  been  found  in 
distant  parts  of  the  body.  This  may  be  useful  in 
keeping  up  the  immunity  of  the  individual  to  these 
intestinal  microbes,  so  long  as  the  microbes  passing 
through  are  of  low  virulence  or  a  virulent.  We  know 
from  experience,  however,  that  if  the  normal  resist- 
ance of  the  intestinal  cells  is  lowered,  these  normal 
intestinal  microbes  are  capable  of  becoming  patho- 
genic, and  such  microbes,  getting  into  the  circulation, 
may  produce  a  general  infection.  This  lowering  of 

71 


Therapeutic  Immunisation. 


resistance  may  be  brought  about  by  too  much  or 
unsuitable  food,  which  may  directly  injure  the 
mucous  membrane  or  suffer  abnormal  decomposi- 
tion by  micro-organisms,  putrefactive  or  otherwise, 
with  the  production  of  poisonous  substances,  which 
may  also  poison  the  organism  as  a  whole.  In  this 
way  a  vicious  circle  is  set  up.  Again,  the  resistance 
of  the  mucous  membrane  may  be  lowered  by  the 
swallowing  of  pathogenic  micro-organisms,  so  that 
very  many  of  the  infections  of  the  intestinal  tract 
are  mixed  ;  while  the  stomach  may  be  invaded  by 
microbes  ascending  from  the  intestine.  Other 
causes  of  lowered  resistance  will  be  considered  when 
dealing  with  the  different  regions  of  the  tract. 

Acute  Infections. 

Typhoid  and  Paratyphoid  Fevers  —  The 
Entericas. — These  conditions  are  general  infections, 
but  as  most  of  the  symptoms  point  to  the 
intestines,  it  is  convenient  to  deal  with  them 
here.  The  symptoms,  physical  signs  and  lesions 
produced  by  the  typhoid  and  paratyphoid  bacilli 
A  and  B  are  practically  identical ;  indeed  the 
condition  may  be  caused  by  a  mixed  infection  with 
the  two  organisms. 

Pathology,- — There  is  a  general  gastroenteritis  with 
superficial  necrosis  of  the  lymphoid  tissue  of  Peyer's 
patches  produced  by  blocking  of  their  afferent 
arterioles.  The  ulceration  may  be  so  deep  as  to  pro- 
duce perforation  of  the  intestinal  wall  and  invasion 
of  the  peritoneum.  The  specific  infection  is  aided 
in  its  depredations  in  the  intestine  by  the  ordinary 

72 


Alimentary  ,Canal. 


microbial  inhabitants  of  the  patient's  intestine 
becoming  pathogenic  owing  to  the  lowered  powers 
of  resistance  of  the  tissues.  The  gall  bladder  and 
spleen,  which  latter  is  usually  enlarged,  are  favourite 
habitats  of  the  typhoid  and  paratyphoid  bacilli. 
Acute  bronchitis  is  common  in  the  disease.  There 
is  a  poly  nuclear  leucopenia. 

Bacteriology. — The  typhoid  and  paratyphoid  A  and 
B  bacilli  are  morphologically  indistinguishable  from 
each  other.  In  the  tissues  they  are  short,  stout 
bacilli  2 — 3  in  length  and  o*6— 0*7  /x  broad  with 
rounded  ends.  In  culture  they  vary  in  size  from 
cocco-bacilli  to  long  filamentous  forms.  They  are 
all  motile  (as  a  rule),  flagellated  and  decolourised  by 
Gram's  method.  They  can  be  distinguished  from 
each  other  by  cultural  reactions  and  agglutination 
tests.  The  chief  sugar  reactions  are  shown  in  the 
following  table  : — 


Glucose 

Lactose 

Saccha- 
rose. 

Man- 
nite. 

Dulcite. 

Litmus  Milk. 

Typhoid  . 

A. 

A. 

—  or 
A.,  then  AUc,  no  clot. 

Paratyphoid  A. 

A.  G. 

A.  G. 

A.  G. 

A.,  no  clot. 

Paratjrphoid  B. 

A.  G. 

A.  G. 

A.  G. 

A.,  then  Alk.,  no  clot. 

A.  =  Acid.    A.  G.  =  Acid  and  Gas.    Alk.  =  Alkaline. 


The  microbe  can  be  isolated  from  the  blood, 
urine,  or  faeces.  Much  the  quickest  method  of 
diagnosis  is  the  isolation  of  the  microbe  from  the 
blood.     This  can  be  done  in  the  majority  of  cases 

73 


Therapeutic  Immunisation. 


if  the  culture  is  taken  during  the  first  few  daj^s 
of  the  illness  or  at  least  before  the  temperature 
begins  to  fall.  Much  the  best  medium  to  use  is 
steriUsed  ox-  or  sheep-  bile,  to  which  the  blood 
withdrawn  from  a  vein  in  the  anticubital  fossa  is 
added.  The  bile  culture  is  subcultured  on  to 
ordinary  agar  ;  the  microbe  obtained  is  diagnosed 
by  sugar  and  agglutination  tests  with  specific  sera. 
If  the  microbe  does  not  appear  on  the  first  sub- 
culture the  process  of  subculturing  should  be 
persisted  in  daily  for  a  week  before  giving  up  hope. 
If  the  patient  has  diarrhoea  the  microbe  can  be 
isolated  easily  on  differential  medium,  such  as 
McConkey's,  but  if  constipated  the  colon  must  be 
cleaned  out  by  enemata  and  the  liquid  faeces  obtained 
after  a  saline  purgative  used  for  culturing.  After 
a  varying  time  the  serum  of  the  patient  strongly 
agglutinates  the  causative  microbe  (Widal  test). 

Prophylaxis,  —  A  great  decrease  in  the  case 
incidence  and  a  marked  decrease  in  the  mortality 
has  been  brought  about  by  prophylactic  inocula- 
tion. The  method  is  used  in  armies  and  those 
going  to  tropical  countries.  The  usual  practice 
is  to  give  500 — 1,000  units  of  typhoid  vaccine  as  a 
first  dose  and  1,000 — 2,000  units  ten  days  after. 
As  a  rule  there  is  little  or  no  reaction.  In  some  indi- 
viduals, however,  there  is  severe  malaise,  rise  of 
temperature,  swelling,  and  pain  at  the  site  of 
inoculation.  Wright,  who  introduced  the  method, 
uses  strains  of  microbes  which  have  been  reactivated 
by  passage  through  guinea-pigs.  Personally,  I 
prefer  to  use  the  first  subculture  of  a  strain  re- 

74 


Alimentary  Canal. 


activated  by  growing  in  broth,  to  which  fresh 
human  blood  has  been  added.  The  subcultures  on 
agar  plates  are  grown  for  twenty-four  hours,  and  the 
suspensions  in  -5  per  cent,  phenol  saKne  are  counted 
on  Thoma  Zeiss  slides.  The  '5  per  cent,  phenol  in 
the  saline  solution  kills  the  typhoid  bacillus,  as  a  rule, 
in  a  day  or  two.  Further,  since  there  is  a  great  lia- 
bility to  paratyphoid  fever,  vaccines  of  paratyphoid 
A  and  B  are  now  generally  given  at  the  same  time. 

I  use  for  the  first  dose  500  million  each  of  para- 
typhoid A  and  B,  followed  by  double  this  dose  in 
five  to  twelve  days,  according  to  the  reaction. 

Treatment. — The  treatment  of  typhoid  and  para- 
typhoid fevers  by  vaccine  has  not  been  so  firmly 
established  as  has  its  use  for  prophylaxis,  although 
good  reports  have  been  published  of  its  influencing 
the  course  of  the  disease  in  the  direction  of  lowering 
the  temperature  and  lessening  liability  to  relapse, 
especially  when  used  early  in  the  disease.  This  is 
probably  due,  as  already  mentioned,  to  the  fact 
that,  when  the  resistance  of  the  intestinal  tissues  is 
lowered  by  the  typhoid  bacillus,  the  coliform  and, 
probably,  other  microbes  present  become  patho- 
genic a  mixed  infection  results.  These  microbes 
increase  the  ulceration  produced  by  sloughing  of 
Peyer's  patches  and  may  bring  about  perforation. 
Coliform  bacilli  can  frequently  be  isolated  from  the 
urine  as  well  as  the  typhoid  bacilli  and  paratyphoid 
bacilli  in  the  entericas.  My  practice  is  to  give  a 
mixed  vaccine  containing  the  patient's  typhoid 
or  paratyphoid  bacilli  and  his  B.  coli  in  equal 
proportions.     In  two  bad  cases  of  paratyphoid 

75 


Therapeutic  Immunisation. 


B  fever,  one  of  which  had  been  a  week  ill,  the  other 
three  weeks,  the  pulse  and  temperature  were  normal 
at  the  end  of  twenty-four  hours,  and  delirum  and 
other  symptoms  had  disappeared.  In  three  cases  of 
typhoid  fever  in  different  stages  the  temperature 
came  down  to  normal  and  remained  there  after  the 
second  injection  of  mixed  vaccine.  The  vaccine  must 
be  autogenous.  The  initial  dose  is  2j  millions, 
and  the  sequence  2|,  5,  7|,  lo,  and  so  on.  The 
vaccine  should  be  continued  until  all  the  typhoid  or 
paratyphoid  bacilli  have  disappeared  from  the  urine 
and  faeces.  The  injection  should  be  given  sub- 
cutaneously  on  the  upper  part  of  the  chest.  The 
general  principles  for  giving  vaccines  in  acute 
injections  should  be  followed  (see  p.  62). 

In  the  treatment  of  carriers  several  thousand 
million  may  have  to  be  attained  and  any  other 
microbe  present,  such  as  the  B.  coli,  included  in  the 
vaccine. 

Antityphoid  sera  are  chiefly  bacteriolytic  and, 
instead  of  being  of  use,  may  even  be  dangerous,  as 
they  bring  about  a  large  amount  of  lysis  of  bacilli 
in  the  body  with  liberation  of  their  toxins,  and  so 
the  patient  may  be  overwhelmed  with  toxin,  since 
there  is  not  sufficient  antitoxin  present  to  neutra- 
lise it. 

Cholera  is  an  acute  gastroenteritis  caused  by 
cholera  vibrio.  Owing  to  copious  watery  evacua- 
tions, the  system  becomes  rapidly  depleted  of  fluid 
and  the  specific  gravity  of  the  blood  becomes 
abnormally  high.  The  microbes  are  said  to  undergo 
rapid  lysis  in  the  blood  stream,  and  so  cannot  be 

76 


Alimentary  Canal. 


isolated  from  it.  They  are,  however,  excreted  in  the 
urine  so  that  there  must  be  a  septicaemia. 

Pathology. — The  lesions  are  most  marked  in  the 
lower  part  of  the  ileum  and  are  those  of  serous 
enteritis.  There  is  desquamation  of  the  superficial 
epithelium  and  coagulation  necrosis  of  the  villi 
with  shght  infiltration  of  the  mucosa  with  leucocytes. 

Bacteriology. — The  cholera  vibrio  is  a  small  curved 
motile  bacillus  with  one  or  more  fiagella  at  one  or 
both  ends.  It  is  i*5 — 3  \x  in  length  and  0*5 — 0*6 
broad.  It  is  Gram-negative.  Its  toxin  outside  the 
body  appears  to  be  an  endotoxin,  but  the  experi- 
ment already  cited  (see  p.  18)  points  to  the  proba- 
bility of  an  exotoxin  being  produced  in  the  body. 
Its  lysis  in  the  blood  must  of  course  liberate  its 
endotoxin.  According  to  some  authorities  most  of 
the  poisonous  effects  are  produced  by  its  manufac- 
ture of  nitrites  in  the  intestines. 

Diagnosis  is  made  by  isolation  of  the  microbe 
from  the  stools.  Their  identity  is  confirmed  by 
agglutination  tests,  Pfeiffer's  phenomenon,  or 
complement  fixation. 

Treatment :  Prophylaxis. — Haffkine's  methods  are 
the  best  known.  In  his  former  method  the  first  two 
injections  consisted  of  usually  J  of  an  agar  slope 
culture  10  c.cm.  long  of  low  virulence.  The  lowering 
of  virulence  was  brought  about  by  Repeated  sub- 
culture and  growth  at  39*6  deg.  C.  The  final  dose 
was  \  of  an  agar  slope  culture,  10  c.cm.  long  of  an 
exalted  strain.  His  present  method  is  to  give  0*5  c.c. 
of  a  suspension  of  an  agar  slope  culture  of  a  virulent 
strain  suspended  in  5  c.c.  of  sterile  water.  The 

77 


Therapeutic  Immunisation. 


exaltation  of  the  virulence  is  brought  by  20 — 30 
passages  through  guinea-pigs.  The  immunity  lasts 
on  an  average  about  a  year.  The  method  has  greatly 
reduced  the  case  incidence  and  has  had  some  effect 
on  case  mortality.  Vaccines  do  not  appear  to  have 
been  used  in  the  treatment.  Probably  in  most  cases 
the  disease  is  too  overwhelming.  However,  vaccine 
ought  to  play  a  useful  role  in  clearing  up  carriers. 
Attempts  have  been  made  to  produce  efficient  anti- 
endotoxicsera  by  various  methods  of  breaking  up  the 
microbes  before  inoculation  ;  their  use  combined 
with  symptomatic  treatment  (hypertonic  salt  solu- 
tion, etc.)  has  given  encouraging  results  in  some  cases. 

Epidemic  Dysentery  is,  as  a  rule,  caused  by 
B.  dysenteries.  Shiga,  Flexner  Kruse  and  others 
have  isolated  similar  bacilli  differing  somewhat 
in  cultural  characteristics  and  in  their  serum  tests. 
But  very  many  other  micro-organisms  are  capable 
of  producing  epidemics  of  acute  gastroenteritis, 
such  as  the  Bacillus  pyocyaneus,  Morgan's  No.  i 
bacillus,  B.  enteridis  of  Gaertner,  and  other  members 
of  the  typhoid-coli  group.  The  acute  outbreaks  of 
diarrhoea  that  occur  on  sudden  changes  of  tempera- 
ture in  the  spring  and  autumn  are  probably  due  to 
the  ordinary  coliform  microbes  of  the  intestinal 
tract,  which  increase  in  virulence  when  the  resistance 
of  the  intestinal  tract  is  lowered. 

Pathology. — As  a  rule  the  onus  of  the  infec- 
tion is  in  the  lower  part  of  the  ileum  and  colon. 
The  mucous  membrane  is  intensely  swollen,  infil- 
trated with  inflammatory  cells,  while,  here  and 
there,  haemorrhages  occur  and  it  is  covered  with 

78 


Alimentary  Canal. 


blood-stained  mucus.  The  infection  may  be  so 
severe  that  the  whole  membrane  may  slough,  and 
the  infection  may  penetrate  to  the  peritoneum. 

Bacteriology. — The  B,  dy sentence  is  a  small  rod- 
shaped,  non-motile  non-flagellated,  Gram-negative 
microbe,  I — 3  in  length.  In  culture  filamentous 
forms  develop.  None  of  the  varieties  isolated  ferment 
lactose,  their  other  sugar  reactions  are  often  variable 
and  the  identity  of  the  various  strains  are  best 
ascertained  by  agglutination  with  specific  sera. 
This  table  contains  the  chief  sugar  reactions  of 
typical  members  of  four  strains. 


Glucose 

Lactose 

Saccha- 
rose. 

Maltose 

Man- 
nite. 

Dulcite. 

Litmus  Milk. 

B.  Dys.  Shiga 

A. 

A.,  then  Alk. 

Flexner 

A. 

A. 

A. 

A.,  then  Alk. 

Y 

A. 

A. 

A.,  then  Alk. 

Strong 

A. 

A. 

A. 

A. 

A. 

A.,  late  Clot. 

A. 

=  Acid. 

Alk.  = 

Alkaline. 

The  toxin  of  Shiga's  bacillus  is  an  endotoxin  which 
is  unusually  thermostable.  It  has  been  obtained  by 
allowing  cultures  to  undergo  autolysis,  by  grinding, 
and  other  methods.  Powerful  agglutinating  bac- 
teriolytic and  antitoxin  sera  have  been  produced. 

In  acute  cases  the  microbe  swarms  in  the  stools, 
the  diagnosis  of  type  being  made  by  cultural 
characteristics  and  agglutination  tests.  In  chronic 
cases  and  carriers  isolation  may  be  more  difficult, 

79 


Therapeutic  Immunisation. 


but  agglutination  of  laboratory  strains  by  the 
patient's  serum  is  helpful,  agglutination  in  a 
dilution  of  1*50  being  a  diagnostic.  The  microbe 
has  also  been  isolated  from  the  blood  and  urine. 

Treatment :  Prophylaxis,  —  Various  sera  have 
proved  their  value  for  prophylactic  purposes,  both 
in  the  laboratory  and  in  practice,  but  o^ving  to  the 
possibility  of  sensitising  the  patient  with  consequent 
anaphylaxis  if  the  patient  should  develop  the  disease 
and  serum  is  used  it  is  much  better  practice  to  use 
vaccine  for  this  purpose.  This  has  been  done  on  a 
large  scale  by  Shiga  and  others,  various  types  of 
vaccine — ordinary,  sensitised,  and  so  on — being  used. 
Shiga's  vaccine  is  made  by  suspending  a  twenty-four- 
hour  agar  slope  culture  in  5  c.c.  normal  saUne,  and 
heating  to  60  deg.  C.  for  an  hour.  The  dose  begins 
with  '05  c.c.  and  rises  to  '5  c.c. ;  by  this  method  he 
has  largely  reduced  the  case  mortaUty,  but  has 
produced  less  effect  on  the  case  incidence. 

Shiga,  Kruse,  and  others  speak  highly  of  the 
excellent  results  produced  by  the  use  of  serum  in 
acute  cases.  Probably  the  results  would  be  greatly 
improved  if  the  serum  treatment  were  combined  with 
autogenous  vaccine  from  the  whole  growth  from  the 
patient's  stools.  The  vaccine  should  be  continued 
until  all  bacilli  disappear  from  the  faeces.  As  one 
would  expect,  serum  is  of  little  use  in  the  chronic 
cases.    Here  vaccine  has  been  most  successful. 

Undoubtedly,  as  in  other  intestinal  infections 
mixed  autogenous  vaccine  should  be  used.  This 
method  should  also  be  used  in  non-specific  dysen- 
teries.  In  those  due  to  coliform  microbes  I  generally 

80 


Alimentary  Canal 


use  an  initial  dose  of  2|  million.  It  is  better  to  give 
the  inoculations  subcutaneously  on  the  chest. 

Regional  Infections. 

Pyorrhoea  Alveolaris. — This  condition  is  an 
inflammation  of  the  gums  around  the  teeth,  varying 
in  intensity  from  slight  catarrh  of  the  tissue  in  the 
small  normal  groove  between  the  apex  of  the  gum 
and  the  teeth  to  complete  destruction  of  the  bony 
alveolus  with  consequent  falling  out  of  the  teeth.  In 
some  cases  the  soft  tissues  of  the  gums  are  swollen 
and  spongy,  and  on  pressure  pus  wells  up  around  the 
tooth,  in  others  the  soft  tissues  are  destroyed  as  well 
as  the  bony  alveolus,  the  tooth  becoming '  stripped.' 

The  condition  is  most  important,  as  it  is  so 
common.  The  constant  swallowing  of  pathogenic 
micro-organisms  infects  the  whole  gastrointestinal 
tract ;  further,  microbes  infect  the  blood  stream 
through  broken  blood  vessels  and  lymphatics,  and  so 
any  tissue  in  the  body  may  become  infected  from 
this  source. 

Bacteriology, — Many  different  kinds  of  microbes 
have  been  isolated  from  the  pus.  The  infection  is 
commonly  a  mixed  one,  the  most  usual  combina- 
tion, in  my  experience,  being  microbes  belonging  to 
the  Micrococcus  catarrhalis  group  and  streptococci. 
Staphylococci  of  various  sorts,  bacilli  related  to 
Friedlander's  pneumobacillus.  Gram  negative  bacilli, 
morphologically  like  the  influenza  bacillus,  but 
differing  from  it  in  its  profuse  growth  on  blood-agar, 
are  also  common.  I  have  found  the  Bacillus  fusi- 
formis  involved  with  other  microbes  in  several  cases. 

T.I.  8i  ^ 


Therapeutic  Immunisation. 


The  diagnosis  of  the  causative  microbe  is  made  by 
(i)  Making  smears  of  the  pus  and  staining  by  Gram's 
method  ;  (2)  Making  cultures  on  blood- agar. 

If  the  smear  shows  the  presence  of  the  Bacillus 
fusiformis  cultures  must  be  made  on  glucose  agar 
and  grown  anaerobically. 

Cultures  may  be  made  from  the  fang  of  a  root  or 
of  a  hopelessly  loose  tooth  or,  faiUng  this,  a  small 
firm  platinum  loop  is  passed  down  into  a  pocket 
alongside  a  tooth  and  jigged  about  until  blood 
appears.  The  loopful  of  blood  and  pus  is  inoculated 
on  to  a  plain  agar  slope.  The  amount  of  blood  in 
the  loop  is  sufficient  so  that  a  special  blood-agar 
need  not  be  made.  As  a  rule  a  good  growth  results 
in  24  or  36  hours.  The  different  colonies  that  grow 
are  picked  off  for  investigation  and  subcultured  on 
to  blood-agar. 

TreaUnent. — It  is  of  course  impossible  to  save  teeth 
from  falling  out  when  the  destruction  of  the  alveolus 
has  gone  beyond  a  certain  point,  but  it  is  remarkable 
how  teeth  tighten  up  sometimes.  It  is  necessary  to 
invoke  the  aid  of  a  painstaking  dentist  who  must 
remove  tartar  with  meticulous  care,  split  down 
pockets  in  order  to  drain  them  and  level  up  a  tooth 
which  is  projecting  beyond  its  fellows  and  is  thus 
exposed  to  abnormal  shocks  and  so  on  ;  even  when 
many  or  all  the  teeth  are  hopelessly  loose  and  have  to 
be  removed,  a  course  of  vaccine  therapy  is  indicated, 
for  it  is  seldom  indeed  that  the  disease  has  lasted 
for  such  a  time  without  causing  lesions  in  other 
tissues,  and  that  it  is  the  source  of  infection  in  many 
diseases  of  these  tissues  there  can  be  little  or  no  doubt. 

82 


Alimentary  Canal. 


The  disease  is  constantly  present  in  diabetes  mellitis, 
pernicious  anaemia  and  most  of  the  chronic  infections 
of  the  gastrointestinal  tract.  It  is  constantly 
present  in  diseases  of  the  spleen,  such  as  Banti's 
disease  and  spleno-meduUary  leucaemia,  the  etiologies 
of  which  are  at  present  obscure.  It  is  seldom  one  finds 
a  case  of  rheumatism  without  it ;  it  is  often  present 
in  phthisis  and  chronic  bronchitis.  It  may  also  be 
the  source  of  origin  of  the  microbes  producing 
rheumatic  fever,  endocarditis  and  acute  and  chronic 
nephritis.  In  many  of  the  diseases  mentioned  I  have 
produced  focal  reactions  by  inoculating  the  patients 
with  vaccines  made  from  microbes  isolated  from  their 
gums. 

For  most  combinations  of  microbes  found  I  begin 
with  a  dose  of  2  J  million  of  a  vaccine  containing  the 
isolated  microbes  in  equal  proportions,  the  usual 
series  being  2|,  5,  7I,  10,  15,  20,  30,  50,  75,  100,  200, 
and  so  on  to  1,000.  I  seldom  like  to  stop  before 
800 — 1,000,  as  this  dose  usually  guarantees  against 
relapse.  I  have  often  had  to  attain  very  much 
larger  doses,  10,000  miUion  or  more.  The  general 
rule  applies,  viz.,  that  there  is  no  fixed  upper  limit  of 
dosage  for  any  case,  each  must  be  worked  out  on  its 
merits.  If  a  staphylococcus  is  isolated  I  begin  with 
25  miUion  of  it,  the  series  being  25,  50,  100,  200,  400, 
600,  and  so  on  up  to  4,000  or  more  but  for  most 
combinations  2|  millions  is  the  best  initial  dose. 
The  intervals  depend  on  the  reaction  and  the  size  of 
the  dose.  Usually  a  few  days  is  sufiicient  between 
the  lower  doses,  gradually  extending  to  a  week  or  ten 
days  between  the  larger.    I  usually  give  the  doses 

83 


Therapeutic  Immunisation. 


on  the  dorsum  ilii  unless  there  is  reason  for  not 
doing  so,  such  as  a  rheumatic  joint  in  the  lower  limb. 

The  vaccine  treatment  of  pyorrhoea  alveolaris 
is  most  satisfactory  as  a  rule. 

Infective  Gastritis  is  brought  about  as  a 
rule  by  the  swallowing  of  pathogenic  microbes  con- 
tained in  infected  material  from  the  nose  tonsils 
or  mouth.  So  that  in  any  case  of  gastric  indiges- 
tion such  a  source  of  infection  should  be  looked  for 
and,  if  present,  it  is  more  than  probable  that  the 
microbes  causing  it  are  the  cause  of  the  gastritis. 
In  some  cases  the  infection  spreads  upward  from 
the  intestine.  It  is  commonly  thought  that  the 
hydrochloric  acid  in  the  gastric  juice  offers  complete 
protection  from  the  action  of  pathogenic  micro- 
organisms. Even  during  the  height  of  digestion  it 
is  probable  that  when  mixed  with  the  food  the 
amount  of  hydrochloric  acid  does  not  rise  above 
0*1  per  cent.,  and  this  strength  is  quite  inadequate 
to  kill  most  microbes  during  the  time  it  is  in  contact 
with  them  in  the  stomach.  In  the  intervals  of 
digestion  hydrochloric  acid  is  not  produced  and, 
therefore,  there  is  no  inhibition  of  the  action  of  any 
microbes  that  may  be  swallowed. 

Pathology. — Infective  gastritis  may  be  acute  or 
chronic,  the  latter  often  being  a  sequel  of  the 
former  ;  acute  exacerbations  of  the  chronic  form 
are  common.  In  the  acute  there  are  the  usual 
changes  seen  in  inflammations  of  mucous  mem- 
brane, viz.,  swelling  and  redness  of  the  mucous 
membrane  with  mucus  lying  on  its  surface.  This 
has  entangled  in  it  leucocytes,  desquamated  epithe- 

84 


Alimentary  Canal. 


Hum  and  red  blood  corpuscles.  The  secretory  cells 
of  the  glands  are  cloudy  and  desquamated,  while 
there  is  small  round-celled  infiltration  between  them. 
The  blood-vessels  are  congested  and  there  may  be 
capillary  haemorrhages.  The  lymphatics  may  also 
show  desquamation  of  their  endothelial  cells.  In 
the  chronic  cases  there  are  minor  degrees  of  those 
changes,  while  if  the  inflammation  is  long  con- 
tinued there  is  an  increasing  degree  of  fibrosis  of  the 
membrane.  The  gastric  juice  is  absent  completely 
or  partly  and  the  condition  is  aggravated  by  the 
abnormal  decomposition  products  produced  from 
the  food  by  microbes. 

Bacteriology. — The  diagnosis  of  the  causative 
microbes  may  be  made  by  plating  out  material 
from  the  stomach  itself  during  fasting  by  passing 
down  a  small  bucket  attached  to  a  flexible  steel 
ribbon,  the  whole  being  enclosed  in  a  rubber 
tube  ;  when  in  the  stomach  the  bucket  is  pushed 
out,  by  means  of  the  ribbon,  from  the  end  of 
the  rubber  tube,  a  sample  of  the  infected  mucus  is 
obtained  and  the  bucket  drawn  back  into  the  tube 
before  being  withdrawn.  As  a  matter  of  practical 
experience  most  cases  of  gastritis  also  suffer  from 
intestinal  inflammation,  so  that  if  cultures  are  made 
from  the  faeces  and  from  the  source  of  infection 
above  one  is  certain  to  obtain  the  right  microbes. 
Since  streptococci  are  the  most  common  causes  of 
lesions  in  the  mouth,  throat  and  respiratory  passages, 
they  are  the  most  common  causes  of  gastritis,  but 
any  of  the  microbes  producing  these  conditions  may 
be  causative.     The  B,  coli  sometimes  spreads  up 

85 


Therapeutic  Immunisation. 


from  the  intestine.  Various  saprophytic  microbes, 
e,g,,  sarcinae,  may  aggravate  the  condition  by  produc- 
ing abnormal  decomposition  of  foodstuffs. 

Prophylaxis, — Prophylaxis  consists  in  clearing  up 
the  sources  of  infection  and  so  preventing  infected 
material  reaching  the  stomach. 

Treatment. — The  quickest  way  of  relieving  the 
symptoms  of  acute  gastritis  is  by  giving  the  patient 
normal  horse  serum  or  any  other  antiserum  ;  anti- 
diphtheritic  serum,  even  if  out  of  date,  does  very 
well.  Ten  c.c.  of  normal  horse  serum  disguised  in  a 
little  milk  given  by  the  mouth  when  the  stomach  is 
empty  the  first  thing  in  the  morning  every  twenty 
four  hours  quickly  reheves  the  symptoms.  Whether 
it  acts  in  a  germicidal  manner  or  by  increasing  the 
resistance  of  the  cells  by  improving  their  nutrition,  has 
not  been  ascertained.  As  soon  as  a  vaccine  is  ready  it 
should  be  used,  the  serum  being  continued  if  necessary. 
If  the  vaccine  consists  of  the  ordinary  catarrhal 
microbes  2|  millions  is  the  ordinary  initial  dose. 
If,  as  is  usually  the  case,  intestinal  inflammation  is 
also  present,  or  if  the  B.  coli  has  invaded  the  stomach 
2|  millions  of  this  vaccine  should  also  be  given. 
The  usual  sequence  is  2|  +  5  +  5>  7i  +  7h 
10  +  10,  15  +  15,  20  +  20,  30  +  30,  50  +  50, 
75  +  75*       +  to  500  +  500  or  more.  In 

acute  cases  it  may  not  be  necessary  to  push  the  dose 
very  high,  but  in  chronic  cases  high  doses  may  have 
to  be  reached  before  the  infection  is  got  rid  of.  It 
is  best  to  inoculate  the  patient  in  the  upper  part  of 
the  body.  Of  course,  appropriate  diet  and  other 
symptomatic  treatment  is  of  the  utmost  importance. 

86 


Alimentary  Canal. 


Gastric  Ulcer. — The  cause  of  this  condition  is 
obscure.  Personally,  I  am  of  the  opinion  that  most 
cases  are  infective  in  origin  and  have  the  same 
etiology  as  infective  gastritis.  In  severe  cases  of 
this  (gastritis)  the  mucous  membrane  may  slough, 
and  it  seems  reasonable  to  suppose  that  in  general 
inflammation  of  the  stomach  the  inflammation  may 
be  more  severe  in  one  place  than  another  and  so  lead 
to  localised  necrosis  partly  due  to  direct  action  of 
microbial  toxins  on  the  cells  and  partly  due  to 
interference  with  the  nervous  and  blood  supply  of 
the  area.  If  the  rest  of  the  mucous  membrane  has 
not  been  involved  or  if  the  inflammation  in  it  sub- 
sides the  action  of  the  digestive  ferment  on  the 
tissues  infected  may  aggravate  the  condition  ;  in 
this  way  what  is  known  as  a  peptic  ulcer  may  arise. 
It  is  doubtful  if  the  pepsin  could  attack  living  cells. 

Pathology, — If  the  ulcer  is  seen  in  the  recent 
acute  phase  there  are  evidences  of  acute  inflamma- 
tion, but  as  usually  seen  the  peptic  ulcer  is  oval 
terraced,  narrowing  to  its  base,  making  it  funnel 
shaped ;  on  section  there  is  a  certain  amount 
of  infiltration  with  leucocytes,  some  fatty  degenera- 
tion and  proliferation  of  the  endotheKum  of  the 
blood  vessels.  This  endarteritis  may  be  caused  by 
poisons  or  microbes  in  the  circulation  and  so  pro- 
duce ulceration.  This  is  generally  thought  to  be 
the  origin  of  the  ulcers  of  the  stomach  and  duo- 
denum that  follow  burns  of  the  skin.  If  the  ulcer  is 
very  chronic  there  may  be  a  great  deal  of  fibrosis, 
and  the  stomach  may  be  adherent  to  adjacent  parts. 

Bacteriology. — See  under  gastritis. 

87 


Therapeutic  Immunisation. 


Treatment. — The  treatment  is  exactly  the  same  as 
for  gastritis  {q.v,).  The  serum  treatment  is  par- 
ticularly effective  in  bringing  about  rapid  heahng 
and  stopping  haemorrhage,  while  immunisation 
removes  the  cause.  Surgical  interference  is  only 
necessary  if  the  ulcer  has  produced  mechanical 
obstruction,  if  there  is  perforation  or  if  the  ulceration 
has  opened  into  a  large  blood-vessel. 

Duodenum. — Lesions  of  the  duodenum  are  of 
particular  importance  because  (i)  in  its  mucous 
membrance  is  produced  the  hormone  or  hormones 
essential  for  the  working  of  the  pancreas  ;  (2)  in  it, 
as  in  the  upper  part  of  the  jejunum,  is  also  produced 
the  enterokinase,  without  which  the  protease  of 
the  pancreas  cannot  work  ;  (3)  into  it  open  the 
ducts  of  the  liver  and  pancreas,  up  which  infec- 
tions are  liable  to  spread  and  infect  these  essential 
organs. 

Etiology, — The  cause  of  infections  and  ulcer  of 
the  duodenum  are  the  same  as  in  the  case  of  the 
stomach  with  the  almost  constant  addition  of 
intestinal  micro-organisms  which  spread  up  when 
the  resistance  of  the  duodenal  tissues  has  been 
lowered  by  the  primary  infection.  As  in  the  case  of 
the  stomach,  unsuitable  food,  or  food  improperly 
prepared  by  the  stomach,  or  hyperacidity  of  the 
chyme,  act  as  predisposing  causes  if  the  infecting 
microbes  are  present,  and  in  this  case  microbes  capable 
of  becoming  pathogenic  have  always  easy  access  to 
the  duodenum  from  lower  down  the  intestine. 

Treatment, — The  treatment  is  exactly  the  same 
as  in  the  case  of  the  stomach,  serum  being  used  for 

88 


Alimentary  Canal. 


the  rapid  amelioration  of  the  symptoms,  while  the 
infecting  microbes  are  isolated  from  the  mouth 
or  respiratory  passage  and  from  the  stools,  and 
vaccines  prepared. 

If  examination  of  the  faeces  indicates  imperfect 
digestion  produced  by  pancreatic  or  hepatic  insuffi- 
ciency it  is  well  to  replace  the  absent  secretions. 

The  Pancreas. — The  pancreas  being  essential  to 
proper  preparation  of  the  food  for  absorption  by  the 
tissues  and  also  for  the  digestion  by  the  tissues  of 
the  absorbed  foodstuffs  it  is  of  the  utmost  importance 
to  keep  it  undamaged.  Inflammation  of  the  inter- 
acinar  connective  tissue  involves  the  cell  islands  of 
Langerhans,  where  most  probably  the  coferments  or 
internal  secretions  for  the  metabolism  of  carbo- 
hydrates, fats,  and  very  possibly,  for  that  of  pro- 
teins, are  produced.  Once  these  cells  are  damaged 
they  can  never  be  replaced.  No  other  cells  of  the 
body  seem  capable  of  taking  on  their  functions,  and 
they  are  comparatively  few  in  number  for  the 
production  of  these  so  essential  substances. 

Pathology, — In  acute  general  infections,  such  as 
typhoid  fever  and  pysemia,  the  secreting  cells 
have  been  seen  in  a  state  varying  from  cloudy 
sweUing  to  fatty  degeneration  and  necrosis,  while 
there  is  a  round-celled  infiltration  in  the  interstitial 
tissue.  I  have  seen  a  case  such  as  this  in  which 
sugar  appeared  in  the  urine.  In  other  cases  of 
septicaemia,  and  in  cases  where  the  gland  becomes 
infected  by  extension  from  the  stomach,  kidney,  or 
other  adjacent  tissue,  there  maybe  general  suppura- 
tion of  the  gland,  and  localised  abscesses,  or  destruc- 

89 


Therapeutic  Immunisation. 


tion  of  blood-vessels  may  give  acute  haemorrhagic 
pancreatitis. 

By  far  the  most  common  forms  of  pancreatitis  are 
the  chronic.  This  may  arise  as  a  blood  infection,  as 
in  the  chronic  septicaemia,  which  often  occurs  in 
pyorrhoea  alveolaris  and  chronic  inflammation  in  the 
gastrointestinal  tract  or  the  infection  may  spread  up 
the  ducts.  Very  frequently,  no  doubt,  both  sources 
of  infection  are  present.  Two  types  of  inflammation 
have  been  described :  (i)  intralobular  and  interacinar, 
involving  the  cell  islets,  and  (2)  the  interlobular  ;  the 
former  may  be  a  sequel  to  the  latter.  In  the  inter- 
acinar type  there  is  small  round-celled  infiltration 
of  the  connective  tissue  which  gradually  passes  into 
fibrosis.  The  small  round  cells  may  invade  the  cell 
islets  or  they  may  be  destroyed  by  the  contraction 
of  the  newly-formed  fibrous  tissue.  In  other  cases 
the  onus  appears  to  fall  on  the  islets  themselves, 
which  may  be  poisoned  by  circulating  toxins,  under- 
going various  degenerations,  e.g.,  hyaline  or  fatty. 

In  the  ascending  inflammation  there  is  infiltration 
followed  by  fibrosis  round  the  ducts,  and  between 
the  lobes  and  lobules,  and  the  interacinar  tissues 
may  escape. 

Bacteriology. — The  microbes  causing  the  lesions 
in  acute  septicaemia,  as  in  typhoid  fever,  staphy- 
lococcal septicaemia,  and  rheumatic  fever,  are 
easily  isolated.  In  chronic  septicaemia  it  will 
usually  be  found  that  they  are  derived  from  areas  of 
local  infection,  such  as  post-nasal  catarrh,  pyorrhoea 
alveolaris,  tonsillitis,  chronic  entero-colitis.  The 
causative  microbe  can  sometimes  be  isolated  from 

90 


Alimentary  Canal. 


the  blood  or  urine.  As  we  have  seen,  there  are  many 
microbes  capable  of  producing  these  lesions,  and  it 
may  be  assumed,  as  a  rule,  if  these  lesions  are 
present,  as  they  practically  always  are,  that  some  or 
all  of  these  microbes  are  causing  the  inflammation  in 
the  pancreas. 

Probably  more  commonly  the  infection  spreads  up 
the  pancreatic  ducts,  the  infection  being  derived 
from  the  microbes  causing  duodenitis.  Inflamma- 
tion in  the  duodenum  may  cause  obstruction  of  the 
combined  opening  of  pancreatic  and  bile  duct,  or  a 
gallstone  in  the  bile  duct  or  ampulla  of  Vater  may 
produce  this  result.  Bile  injected  experimentally 
into  the  pancreatic  duct  has  produced  inflammation 
of  the  pancreas.  Chronic  inflammation  of  the  duct 
may  produce  phosphatic  calculi  in  it  and  bring  about 
partial  obstruction. 

In  these  cases  the  intralobular  connective  tissue 
is  involved  last.  As  we  have  seen,  the  causes  of  the 
duodenitis  are  swallowed  microbes,  while  intestinal 
microbes  may  spread  upwards.  So  that  the  causa- 
tive microbes  can  be  isolated  from  these  sources. 
That  this  is  the  case  it  is  open  to  any  one  to  prove  by 
producing  focal  reactions  with  vaccines  made  from 
microbes  isolated  from  these  sources.  This  reaction 
is  easily  followed  in  diabetes,  where  an  injection  of 
vaccine  is  almost  invariably  followed  by  an  in- 
creased excretion  of  sugar,  often  accompanied  by  a 
sHght  tenderness  over  the  pancreas. 

Prophylaxis.  —  Since  the  pancreas  is  probably 
irretrievably  damaged  when  symptoms  appear  it 
is  of  the  utmost  importance  to  prevent  the  infection. 

91 


Therapeutic  Immunisation. 


Except  in  acute  septicaemias  this  ought  always 
to  be  possible.  The  clearing  up  of  the  sources 
of  infection  when  they  occur  will  absolutely  prevent 
the  inflammation.  An  intestinal  vaccine  should  be 
used  if  there  is  any  sign  of  intestinal  derangement. 

Treatment, — If  the  inflammation  has  not  gone 
much  beyond  the  ducts  it  can  be  quite  cleared  up 
with  vaccines  made  from  the  two  sources  of  infection. 
If  the  destruction  has  gone  to  the  extent  of  involving 
the  cell  islets,  with  the  appearance  of  sugar  in  the 
urine,  it  is  only  very  exceptionally  that  the  pancreas 
can  be  sufficiently  restored  so  as  to  cause  this 
symptom  to  disappear  with  an  ordinary  diet.  A  few 
cases  of  diabetes  in  cases  of  furunculosis  have  been 
recovered  by  clearing  up  the  furunculosis  with  staphy- 
lococcus vaccine.  It  is  known,  too,  that  the  removal 
of  the  source  of  infection  such  as  a  gangrenous  limb 
has  also  caused  the  sugar  to  disappear.  As  a  rule, 
however,  the  pancreas  is  irretrievably  damaged,  and 
it  is  only  possible  to  prevent  further  destruction. 

It  is  particularly  difficult  to  sufficiently  immunise 
diabetics.  They  get  general  and  focal  reactions 
with  doses  that  would  have  little  effect  on  other 
patients.  This  is  probably  owing  to  the  pancreas 
being  an  important  source  of  immune  body  or  cofer- 
ment.  It  is  consequently  necessary  to  begin  with 
a  much  smaller  dose,  to  increase  the  dose  slowly, 
and  it  is  in  my  experience  impossible  to  push  the 
dose  beyond  a  very  low  maximum. 

In  the  most  common  case  where  the  vaccines  consist 
of  Micrococcus  catarrhalis  and  streptococci  from  the 
gums  and  coliform  bacilli  from  the  intestines,  an 

92 


Alimentary  Canal. 


initial  dose  of  i  +  i,  followed  at  suitable  intervals 
by  2  +  2/3  +  3,  4  +  4,  6  +  6,  8  +  8,  10  +  10,  and 
so  on,  if  possible.  I  find  I  cannot  usually  get  much 
beyond  the  latter  dose.  I  have  never  entirely 
cleared  up  the  pyorrhoea  alveolaris  of  a  diabetic, 
but  I  have  very  greatly  improved  it,  and  the 
patients  have  all  improved  in  general  health.  Of 
course,  pancreatic  extract  must  be  given  to  supple- 
ment as  far  as  possible  the  diminished  pancreatic 
secretions. 

In  the  ordinary  cases  of  chronic  pancreatitis,  where 
there  is  no  symptom  of  involvement  of  the  intra- 
lobular tissue  the  usual  dosage  may  be  used.  In  the 
case  of  the  microbes  given  above  and  for  practically 
all  microbes  from  these  sources,  2|  +  2j,  5  -f  5, 
10  +  10,  and  so  on,  as  in  the  case  of  duodenitis, 
may  be  used. 

In  typhoid  and  other  septicaemias  the  method  of 
dosage  recommended  in  these  infections  should  be 
used. 

The  Liver. — The  Uver  can  be  infected  by  (i)  direct 
extension;  (2)  through  the  hepatic  artery;  (3)  through 
the  portal  vein;  and  (4)  by  extension  up  its  ducts.  It 
probably  can  deal  better  than  most  organs  with 
micro-organisms,  for  it  must  constantly  have  them 
carried  to  it  by  the  portal  vein.  Whether  the  liver 
cells  can  ingest  and  digest  microbes  is  not  known 
certainly,  the  star  cells  of  Kupffer  and  the  various 
endotheUal  cells  can,  and  it  is  well  known  that  in 
general  infections,  such  as  typhoid  fever,  microbes 
are  excreted  in  the  bile.  The  liver  seems  to  have 
a  special  faculty  for  recovery  from  destruction  of 

93 


Therapeutic  Immunisation. 


its  cells,  for  destroyed  cells  seem  to  be  replaced  by 
proliferation  of  surviving  cells.  It  is  surprising, 
too,  how  comparatively  well  the  individual  can 
remain  when  his  liver  is  badly  damaged  as  in 
cirrhosis.  Acute  inflammation  occurs  in  the  course 
of  general  infections,  such  as  typhoid  fever,  puerperal 
septicaemia,  and  the  like.  In  chronic  inflammation 
the  usual  source  is  infection  from  the  portal  vein, 
which  is  probably  the  cause  in  ordinary  cirrhosis, 
or  by  extension  up  the  duct. 

Pathology, — In  general  infections  the  parenchyma 
cells  may  be  in  a  condition  of  cloudy  swelling,  with 
their  cells  undergoing  fatty  degeneration  or  necrosis, 
and  there  is  round-celled  infiltration  in  or  about 
the  portal  canals  and  between  the  liver  cells. 

Abscess  formation  may  occur  by  direct  extension 
of  infection,  by  infection  through  the  hepatic  artery, 
portal  vein  or  bile  ducts.  It  is  nearly  always 
secondary  to  suppuration  elsewhere. 

Chronic  infection  leading  to  interstitial  hepatitis 
and  cirrhosis  takes  place  through  the  portal  vein. 
This  is  probably  predisposed  to  by  abnormal  amounts 
of  poisonous  substances  produced  by  abnormal 
breakdown  products  of  foodstuffs  by  microbes. 
The  catarrhal  inflammation  of  the  intestine  and  the 
cirrhosis  may  be  predisposed  to  by  the  ingestion  of 
abnormal  amounts  of  irritants,  such  as  alcohol. 

Bacteriology,  —  As  the  liver  inflammation  is 
secondary  to  infections  elsewhere  the  micro- 
organisms producing  these  will  be  the  cause  of 
the  liver  condition. 

Prophylaxis, — Cirrhosis  of  the  liver  could  probably 

94 


Alimentary  CanaL 


be  prevented  by  clearing  up  the  catarrh  of  the 
intestine.  Chronic  infection  via  the  portal  vein  or 
bile  duct  could  be  prevented  in  the  same  way. 

Treatment. — Nothing  special  need  be  said  about 
the  treatment  of  the  liver  infections  by  vaccines, 
as  they  are  always  secondary  and  the  microbes  must 
be  isolated  from  the  source  of  the  infection.  Nor  is 
there  any  modification  of  the  course  of  inoculation 
to  be  observed  on  account  of  the  liver  being  involved. 

The  Gall  Bladder  and  Bile  Ducts. — Chole- 
cystitis and  cholangitis  are  most  commonly  pro- 
duced by  infection  ascending  from  the  duodenum. 
In  certain  cases  they  are  produced  by  microbes 
excreted  by  the  liver.  This  occurs  frequently  in  the 
ent ericas.  The  gall  bladder  and  ducts  may,  of  course, 
also  be  infected  through  the  blood  stream  and  by 
direct  extension. 

There  are  three  points  of  special  interest  in  con- 
nection with  infection  of  these  structures,  viz.  : 
(i)  The  production  of  jaundice  ;  (2)  the  formation  of 
gallstones  ;  (3)  the  persistence  of  the  microbe  in  the 
gall  bladder  after  certain  infections,  especially  the 
entericas,  cholera,  and  microbic  dysentery. 

Jaundice. — Pathology. — In  jaundice  produced  by 
catarrhal  inflammation  the  infection  usually  ascends 
from  the  duodenum  and  the  infecting  micro- 
organisms can  be  obtained  from  any  source  of  infec- 
tion above  and  from  the  faeces.  The  mucous  mem- 
brane of  the  bile  duct  is  swollen  and  there  is  a  plug 
of  mucus  in  the  ampulla  of  Vater.  The  ducts  are 
distended  with  bile  and  the  liver  enlarged  somewhat. 

Treatment, — When,  as   is   usual,  the  microbes 

95 


Therapeutic  Immunisation. 


involved  are  the  ordinary  catarrhal  microbes,  the 
most  common,  as  we  have  seen,  being  M.  catarrhalis 
and  streptococci  plus  coliform  baciUi,  the  initial  dose 
should  be  2|  +  2|  million,  and  the  series  5  +  5, 
7i  +  7h  +  15  +  15,  20  +  20.  This  method 
will  be  found  to  cut  short  these  usually  tedious  cases 
in  a  most  satisfactory  manner. 

Gallstones. — Pathology. — Gallstones  are,  with 
few  exceptions,  caused  by  infection  of  the  gall 
bladder  with  microbes  of  the  typhoid-coU  group. 
The  chronic  inflammation  leads  to  increased  excre- 
tion of  cholesterin,  mucinous  material,  and  to 
stagnation  of  the  bile. 

B,  coli  spreads  up  from  the  duodenum  during 
chronic  inflammation  of  it.  Typhoid  and  para- 
typhoid bacilli  lurk  in  the  bile  passages  after  they 
have  disappeared  elsewhere.  The  multiplication  of  the 
typhoid-coU  group  of  microbes  is  favoured  by  bile. 

Prophylaxis  consists  in  clearing  up  inflamma- 
tion of  the  duodenum  by  vaccines  and  treating 
typhoid  and  paratyphoid  fever  with  vaccine. 

Treatment. — It  is  possible  that  gallstones,  if  they 
are  not  too  large  and  if  one  is  not  impacted,  might  be 
got  rid  of  by  exhibition  of  oleic  acid  and  by  use  of 
vaccine  made  from  the  patient's  faecal  microbes. 
If  the  stones  have  to  be  removed  by  surgical  methods 
the  bacteriology  of  the  gall  bladder  should  always  be 
investigated  and  if  microbes  are  present  a  vaccine 
used.  Otherwise  there  can  be  no  guarantee  that  more 
gallstones  may  not  form. 

Enterica  Carriers.  —  As  just  stated  the  gall 
bladder  is   a   favourable   environment   for  the 

96 


Alimentary  Canal. 


growth  and  persistence  of  typhoid  and  paratyphoid 
bacilli,  the  microbes  being  excreted  into  the  bowel 
and  passing  out  with  the  faeces.  Many  epidemics 
have  been  produced  by  cooks,  dairymaids,  and  others 
engaged  in  food  preparation,  who  are  carriers. 

In  other  of  these  cases  the  infection  remains  as  a 
chronic  pyelonephritis,  the  microbes  being  excreted 
in  the  urine.    (See  Typhoid  Fever.) 

Prophylaxis  and  treatment  has  been  discussed 
under  typhoid  fever. 

Appendicitis.- — While  foreign  bodies,  such  as 
faecal  concretions,  may  act  as  predisposing  causes  by 
lowering  the  resistance  of  the  appendicular  tissues  by 
direct  injury  of  the  cells  or  by  interfering  with  the 
circulation,  there  can  be  no  doubt  that  the  lesions 
themselves  are  microbial  in  origin. 

Pathology, — The  histological  changes  may  be  chiefly 
confined  to  the  mucous  membrane  as  in  catarrhal 
appendicitis,  where  there  is  a  mucopurulent  exudate 
into  the  lumen  of  the  organ  and  infiltration  of  the 
mucous  membrane  with  leucocytes,  or  the  inflamma- 
tion may  involve  all  the  tissues  which  are  infiltrated 
with  leucocytes  and  there  is  marked  proliferation  of 
the  lymphoid  cells.  In  these  generalised  cases  the 
swollen  appendix  is  covered  with  plastic  lymph. 
In  cases  where  there  is  a  foreign  body  there  is 
ulceration  where  this  is  in  contact  with  the  tissues. 

The  ulcer  frequently  deepens,  perforation  occurs, 
and  the  foreign  body  is  discharged  into  the  peri- 
toneal cavity.  In  the  worst  cases  the  tissues  are 
completely  destroyed  by  the  microbes  and  become 
gangrenous.    In  the  last  two  cases  there  is  either 

T.I.  7 


Therapeutic  Immunisation. 


general  peritonitis  or  an  abscess  is  formed  by 
matting  together  of  the  intestines  by  plastic  inflam- 
mation and  the  infection  thus  localised. 

Bacteriology. — In  practically  all  cases  B,  coli 
can  be  isolated  from  the  pus  of  an  appendicular 
abscess,  and  unless  the  pus  is  carefully  plated  out 
the  other  microbes  almost  invariably  present  may 
not  grow,  as  they  are  overwhelmed  by  the  profuse 
growth  of  the  B,  coli.  Sometimes  this  occurs  in  the 
body  and  the  other  microbes  have  disappeared  when 
the  culture  is  made.  The  microbes  commonly  found 
are  streptococci  and  staphylococci.  One  or  other  of 
them  is  probably  the  primary  infection  and  is  carried 
to  the  appendix  through  the  blood,  or  probably 
most  commonly  along  the  intestines.  In  most  cases 
of  appendicitis  there  is,  as  in  other  gastrointestinal 
infections,  a  source  of  infection  above  in  the  pos- 
terior nares  tonsils  or  gums ;  these  microbes  lower 
the  resistance  of  the  appendix  and  the  Bacillus  coli 
becomes  pathogenic.  In  exceptional  cases  the 
pneumocor.cus,  B.  pyocyaneus,  B.  typhosus  and 
paratyphosus  have  been  isolated  in  pure  culture. 

Treatment. — As  in  other  infections  of  the  gastro- 
intestinal tract  and  its  adnexa,  if  the  sources  of 
infection  were  removed  by  means  of  immunisation 
with  the  causative  microbes,  the  infection  would, 
of  course,  not  occur.  Vaccines  from  these  sources 
will  permanently  cure  mild  cases  of  appendicitis  and 
remove  the  necessity,  at  present  generally  recog- 
nised, for  operation  during  the  quiescent  period. 
In  fulminating  cases  and  in  cases  of  abscess  forma- 
tion immediate  operation  is  necessary.  Cultures 

98 


Alimentary  Canal. 


should  always  be  made  at  the  time  of  operation  and 
a  vaccine  prepared  as  soon  as  possible.  In  the  usual 
case  of  B,  coli  and  streptococci  growing,  the  initial 
dose  may  be  2^  +  2j  million  of  the  mixed  vaccine, 
and  the  series  3  +  5>  7i  +  7h  +  lo,  15  +  15, 
and  20  +  20,  etc.,  at  appropriate  intervals,  according 
to  the  reaction.  If  staphylococci  grow  the  initial 
dose  is  25  million,  and  the  series  25  +  2|,  50  +  5, 
75  +  7h  +  150  +  15,  200  +  20.  The 
inoculations  are  best  given  on  the  upper  part  of  the 
chest ;  I  +  I  of  streptococci  and  B.  coli  is  the  best 
initial  dose  for  a  child  and  10  +  i  if  staphylococci 
are  present.  This  procedure  saves  many  lives  and 
greatly  reduces  the  period  of  convalescence. 

The  Colon. — Since  certain  surgeons  seem  to  think 
that  the  colon  can  be  very  well  done  without,  it  will 
not  be  out  of  place  to  give  a  brief  description  of  the 
physiology  of  this  part  of  the  alimentary  canal  in  man. 

Its  functions  are  three  in  number :  absorption  of 
water  and  foodstuffs,  excretion  of  waste  products, 
preparation  and  lubrication  of  unused  and  unusable 
material  for  defaecation. 

The  absorption  by  the  large  intestine  is  chiefly 
confined  to  water.  According  to  Starling  about 
500  c.c.  pass  the  ileocolic  valve  in  twenty-four  hours ; 
about  400  c.c.  of  these  are  absorbed  in  the  colon, 
chiefly  in  the  caecum,  ascending,  transverse  and  upper 
part  of  the  descending  colon.  Of  foodstuffs  practi- 
cally only  glucose  is  absorbed. 

The  chief  excretory  function  of  the  large  intestine 
in  man  is  the  excretion  of  lime,  magnesium,  iron  and 
phosphates.    In  man  about  70  per  cent,  of  the  lime 

99 


Therapeutic  Immunisation. 


and  50  per  cent,  of  the  magnesium  leaving  the 
body  is  contained  in  the  faeces.  Most  of  the  iron 
excreted  by  the  body  is  excreted  in  the  fseces. 

Bismuth  and  mercury  given  medicinally  are  chiefly 
excreted  by  the  colon. 

The  chief  secretion  of  the  colon  is  mucus  produced 
by  the  goblet  cells  of  its  tubular  glands. 

It  is  important  then  to  keep  this  excretory  organ 
in  good  order. 

Infections. — The  specific  infections  have  been 
already  dealt  with.  Most  of  the  other  inflammations 
are  part  of  a  general  gastro-entero-colitis.  There 
are  two  conditions,  however,  which  call  for  special 
mention:  they  are  (i)  chronic  constipation  or,  as 
it  is  called  at  present,  intestinal  stasis  ;  (2)  mucous 
colitis. 

Whatever  the  primary  cause  of  constipation,  such 
as  a  diet  containing  too  little  indigestible  material, 
for  instance,  cellulose  or  astringents,  such  as  tannin 
in  tea,  or  substances  interfering  with  the  neuro-mus- 
cular  mechanism,  or,  chief  of  all  causes,  failure  to  go 
regularly  to  stool,  there  can  be  no  doubt  that  when  the 
resistance  of  the  mucous  membrane  is  lowered  by 
[a)  direct  pressure  of  the  faecal  masses,  and  {b)  by  being 
poisoned  by  the  reabsorption  of  excreted  products, 
{c)  infection  from  above,  or  as  a  sequel  to  a  specific 
infection,  the  ordinary  intestinal  microbes  become 
pathogenic  and  produce  inflammation  of  the  mucous 
membrane.  So  that  in  a  case  of  intestinal  stasis  it 
will  be  found  that  there  is  evidence  of  this  action 
both  in  the  mucous  membrane,  which  may  be 
ulcerated  in  the  pouches,  in  the  musculature  of  the 

100 


Alimentary  Canal. 


colon,  and  frequently  evidence  of  chronic  inflamma- 
tion in  its  peritoneal  covering,  e.g.,  formation  of 
adhesions  and  membranes.  In  these  cases,  too, 
there  is  abnormal  decomposition  of  foodstuffs  by 
microbes,  evidenced  by  constant  production  and 
passage  of  large  quantities  of  foul-smelling  gases. 

The  general  condition  of  the  patient  is  poor.  He, 
or  more  often  she,  appears  pale,  pasty  and  has 
foul  breath.  The  patient  is  neurasthenic  and  easily 
tired. 

The  symptoms  are  aggravated  in  the  more  intense 
degree  of  this  condition  known  as  mucous  colitis ; 
sometimes  there  is  diarrhoea  in  this  disease,  more 
often  the  patient  suffers  from  chronic  constipation. 
When  the  hard  masses  are  passed  there  is  a  large 
excretion  of  mucous  on  their  surface ;  in  the  worst 
cases  complete  casts  of  portions  of  the  colon  come 
away. 

Treatment. — It  will  be  frequently  found,  not  only 
in  cases  of  mucous  colitis,  but  also  in  cases  of 
ordinary  constipation,  that  there  is  a  source  of  infec- 
tion capable  of  infecting  the  gastrointestinal  tract. 
The  vaccine  must  then  be  made  from  the  microbes 
isolated  from  this  source  as  well  as  from  the  faeces 
or  mucus  passed  with  them.  As  in  other  cases,  the 
faecal  vaccine  is  made  from  the  mixed  aerobic  growth 
on  agar  plates,  and  the  initial  dose,  2|  million  of  each 
vaccine  and  the  series  5  +  5,  7I  +  71,  10  +  10,  etc., 
a  dose  of  500  +  500  or  more  should  be  reached. 
It  is  well  to  empty  completely  the  colon,  if  necessary, 
by  washing  it  out  thoroughly  before  the  initial  dose, 
otherwise  a  focal  reaction  in  the  colon  may  be  very 

lOI 


Therapeutic  Immunisation. 


painful.  Of  course  the  ordinary  medicinal  aids  must 
be  used.  Liquid  paraffin  is  a  great  stand-by,  and  it 
ought  not  to  be  forgotten  that  spleen  extract 
stimulates  both  the  musculature  and  the  glands  of 
the  colon  and  pituitary  extract  the  muscular  coats. 
Seldom,  indeed,  in  these  cases  ought  it  to  be  necessary 
to  risk  the  patient's  life  by  the  dangerous  operation 
of  colectomy. 

Ischiorectal  Abscess. — Vaccines  made  from  the 
microbes  isolated  from  the  pus  of  ischiorectal 
abscesses,  usually  caused  by  a  mixed  infection,  com- 
monly B,  coli  and  staphylococci  or  streptococci,  will 
rapidly  bring  about  heaUng  if  used  at  once  after 
opening.  If  the  sinus  is  allowed  to  become  chronic  a 
very  large  dose  may  have  to  be  attained  before  cure 
results.  If  the  sinus  opens  into  the  rectum  an 
operation  to  close  this  will  be  sometimes  necessary, 
but  this  ought  not  to  be  done  until  the  patient's 
resistance  to  the  infecting  microbes  is  raised,  as  it  will 
then  have  a  much  better  chance  of  success. 


102 


CHAPTER  VII. 


RESPIRATORY  SYSTEM. 

Diphtheria  is  caused  by  the  B,  diphthericB , 
which  produces  a  superficial  necrosis  of  the  mucous 
membrane,  usually  starting  in  the  upper  respiratory 
tract,  commonly  on  the  tonsils,  fauces  or  pharynx. 
The  inflammation  may  spread  up  into  the  nose, 
down  into  the  tracjiea  and  bronchi,  more  rarely 
down  the  oesophagus.  Quite  commonly  it  spreads 
over  the  uvula  and  soft  palate,  and  may  infect  the 
skin,  especially  on  the  hands,  if  there  is  a  superficial 
abrasion.  The  infection  may  be  conveyed  by  the 
fingers  to  other  mucous  membranes,  such  as  that 
of  the  vulva  and  vagina. 

Pathology, — The  membrane  consists  of  cellulo- 
fibrinous  inflammatorj^  exudate,  enmeshing  the 
tissues  which  have  undergone  necrosis,  the  epithe- 
lium of  the  part  having  been  previously  cast  off. 
Underneath  it  the  blood-vessels  and  lymphatics  are 
distended  ;  there  is  cellular  and  fibrinous  exudate 
and  the  glands  are  blocked  with  exudate  and 
desquamated  cells.  The  B,  diphtherice  or  Klebs- 
Loefifler  bacillus  is  mostly  confined  to  the  superficial 
tissues,  few  of  them  getting  into  the  circulation  ;  the 
general  symptoms  and  the  various  paralyses  which 
often  supervene  being  due  to  the  soluble  toxins  which 
this  microbe  produces. 

Bacteriology, — The  bacillus  is  a  highly  pleomorphic, 
103 


Therapeutic  Immunisation. 

Gram-positive,  non-motile  bacillus,  varying  in  length 
from  a  cocco-bacillus  to  one  4 — 5  /x  in  length; 
it  often  stains  unequally  along  its  length,  giving 
it  a  beaded  appearance.  When  characteristic 
it  is  larger  at  one  end  than  the  other  and  slightly 
curved.  On  suitable  media  branching  forms  develop. 
Its  morphology  is  determined  largely  by  its 
environment.  Loeffler's  serum-glucose  medium  is 
best  for  producing  the  characteristic  '  diphtheroid  ' 
shape. 

This  microbe  is  pleomorphic,  and  the  true  diph- 
theria bacillus  is  resembled  by  morphologically 
similar  microbes,  the  only  difference  being  in  their 
capacity  for  producing  the  characteristic  toxin.  Con- 
sequently, the  only  absolute  test  is  an  immunity 
one.  Equal  doses  of  the  suspected  microbe  are 
injected  into  two  guinea-pigs,  one  of  the  animals 
being  protected  by  a  dose  of  antitoxic  serum  given 
at  the  same  time.  If  the  protected  animal  lives 
and  the  other  dies,  then  the  microbe  dealt  with  is 
the  diphtheria  bacillus. 

For  practical  purposes,  diphtheroid  bacilli  isolated 
from  the  throat  of  a  patient  suffering  from  mem- 
branous inflammation  may  be  taken  as  true  diph- 
theria bacilli.  The  crucial  test  is  necessary  for  the 
diagnosis  of  diphtheria  carriers,  that  is,  apparently 
healthy  persons  who  harbour  diphtheroid  bacilli 
in  their  throats,  as  frequently  occurs  during  an  epi- 
demic, and  frequently  after  an  attack  of  the  disease. 

Immunity. — The  body  probably  chiefly  relies  for 
its  protection  on  antitoxin,  which  g,lso  enables  the 
diphtheria  bacillus  to  be  phagocyted.    No  doubt 

104 


Respiratory  System. 


immune-body  and  heat-labile  opsonin  is  also  formed 
in  small  amounts,  for,  as  we  have  seen,  only  a  few 
bacilli  seem  to  get  into  the  circulation. 

Prophylaxis, — The  common  practice  is  to  give 
500  units  of  antitoxic  serum  to  the  members  of  a 
household  or  of  a  school  in  which  a  case  of  diphtheria 
occurs.  This  seems  to  me  a  doubtful  practice, 
owing  to  the  danger  of  producing  anaphylaxis  when 
serum  is  used  should  one  of  these  patients  develop 
the  disease.  A  much  better  plan  would  be  to  use  a 
vaccine  for  this  purpose.  A  dose  of  10  million 
for  a  child  and  20  million  for  an  adult  may  be  used, 
or  a  small  dose  of  toxin  might  be  used. 

Treatment, — For  the  treatment  of  the  disease 
at  least  2,000  units  should  be  at  once  given  to  a  child 
and  4,000  to  8,000  units  to  an  adult,  and  should  be 
repeated  until  the  membrane  disappears. 

Serum  rashes  which  may  develop  after  an  interval 
are  rapidly  got  rid  of  by  giving  |  to  i  c.c.  of 
pituitrin.  Should  anaphylaxis  develop  the  patient 
should  be  given  at  once  to  i  c.c.  of  pituitrin,  and 
the  dose  repeated  at  once  if  the  symptoms  return. 
The  exhibition  rapidly  relieves  the  terrible  bronchial 
spasm  and  other  symptoms.  If  the  bacilli  are  slow 
to  disappear  from  the  throat,  as  they  frequently  are, 
one  or  two  doses  of  mixed  autogenous  vaccine  made 
from  microbes  grown  from  the  throat  rapidly  brings 
about  their  disappearance.  A  dose  of  2\  million 
for  a  child  and  5  million  for  an  adult  are  average 
initial  doses.  The  progression  is  2|,  5,  7I,  10,  15,  20. 
As  a  rule  the  infection  has  cleared  by  the  time  the 
10  million  dose  is  reached. 

105 


Therapeutic  Immunisation. 


Inflammations  of  Nasal  Passages,  their  Acces- 
sory Sinuses,  Larynx,  Trachea  and  Bronchi. 

There  are  a  great  many  different  microbes  infecting 
the  respiratory  passages.  They  produce  catarrhal 
inflammation  which  varies  from  a  shghtly  increased 
production  of  mucus  to  ulceration  and  destruction 
of  the  underlying  tissues.  The  openings  of  the  sinuses 
may  become  closed,  leading  to  the  production  of 
empyemata. 

In  Acute  and  Chronic  Catarrh  of  the  Nose 
the  sinuses  probably  always  are  involved.  The  infec- 
tions are  important,  as  they  interfere  with  respiration, 
frequently  spread  down  into  the  bronchi,  and  swal- 
lowing of  the  microbes  infects  the  gastrointestinal 
tract  and  the  central  nervous  system  through  the 
ethmoidal  plate. 

Pathology, — In  acute  infections  the  mucous  mem- 
brane becomes  swollen  and  cells  of  the  epithelium 
become  cast  off ;  an  abnormal  number  of  these  cells 
turn  into  goblet  cells  and  pour  their  mucus  on  the 
surface,  which  is  mixed  with  a  serous  exudate  and 
leucocytes.  The  blood-vessels  beneath  the  epithelium 
are  engorged  and  there  is  a  serous  and  cellular 
exudate  into  the  submucous  tissues. 

Similar  changes  occur  in  the  larynx,  trachea  and 
bronchi  in  acute  infections.  Most  commonly  such 
an  infection  begins  in  one  part  of  the  respiratory 
tract  and  spreads  rapidly  along  the  mucous 
membrane. 

In  chronic  infections  there  is  a  generalised  cellular 
io6 


Respiratory  System. 


infiltration  which  leads  to  thickening  of  the  mucosa. 
The  goblet  cells  and  glands  continue  to  overact,  so 
that  there  is  a  chronic  mucous  discharge  containing 
a  varying  amount  of  desquamated  cells  and  pus  cells. 
In  the  nose  this  thickening  is  especially  great  over  the 
inferior  turbinals. 

Later,  the  sero-cellular  exudate  begins  to  contract 
owing  to  the  formation  of  fibrous  tissue,  and  an 
atrophic  condition  may  result.  In  the  nose  this  may 
result  in  atrophy  of  the  bones.  If  the  condition  is 
due  to  the  ozaena  bacillus,  the  muco-pus  and  scabs 
produced  by  its  drying  have  a  characteristically 
foul  odour. 

In  the  bronchi  there  is  cellular  infiltration  of  the 
whole  wall,  and  the  inflammation  may  spread  to  the 
peribronchial  tissues,  leading  to  peribronchial  fibrosis. 
In  places  the  wall  of  the  bronchus  may  become  so 
weakened  that  dilatation  (bronchiectasis)  takes  place. 
Similar  hypertrophy  and  atrophic  changes  occur  in 
the  larynx. 

Bacteriology, — Numerous  microbes  are  capable  of 
producing  epidemics  of  colds  as  well  as  chronic  in- 
fections. Very  frequently  the  infection  is  mixed,  the 
most  common  combination  being  the  M,  catarrhalis 
and  streptococci,  pneumococci,  the  B,  influenzce, 
B,  pertussis,  staphylococci  of  various  kinds.  Fried- 
lander's  pneumobacillus,  Micrococcus  meningitidis, 
the  B.  septus,  diphtheroid  bacilli,  the  ozaena  bacillus. 
I  have  several  times  found  a  small  non-motile 
Gram- negative  bacillus  resembling  the  influenza 
bacillus  in  appearance,  but  differing  from  it  in  its 
abundant  growth  on  blood- agar.    M.  tetragegenus 

107 


Therapeutic  Immunisation. 


and  paratetragenus,  B.  pyocyaneus  and  B.  coli  occur 
sometimes,  and  the  typhoid  and  paratyphoid  A  and 
B  baciUi  in  the  bronchitis  that  often  occurs  in  these 
diseases. 

Staphylococcus. — Staphylococci  are  strongly  Gram- 
positive  spherical  cocci  about  '9  in  diameter.  They 
grow  rapidly  in  opaque,  sharply-outlined  colonies. 
They  are  classified  into  5.  aureus  if  the  colonies  are 
orange-yellow,  5.  citreus  if  lemon-yellow,  5.  albus  if 
milky  white.  When  spread  on  a  slide  they  adhere  in 
little  clumps,  so  that  they  appear  when  stained 
somewhat  like  bunches  of  grapes.   Hence  the  name. 

The  three  above  all  liquefy  gelatine. 

On  blood-agar  some  strains  are  lytic  to  the  haemo- 
globin, others  not. 

Pneumococcus, — The  pneumococcus  is  a  Gram- 
positive  coccus  about  i  /u.  in  length  which  usually 
grows  in  pairs  (diplococcus) .  Each  coccus  is,  when 
typical,  lanceolate  in  shape,  and  the  thick  ends  of  the 
cocci  are  approximated  in  the  pairs.  The  cocci  are 
frequently  surrounded  by  a  capsule  of  clear  material 
which  is  not  stained  by  Gram's  method. 

They  grow  as  small  transparent,  clear-cut  colonies 
on  blood-agar,  not  attaining  a  size  greater  than 
I  mm.  as  a  rule. 

When  grown  in  broth  they  sometimes  form  short 
chains,  so  that  it  is  difficult  to  distinguish  them  from 
streptococci,  to  which  they  are  closely  related. 
Pneumococci  are  said  to  be  distinguished  from 
streptococci  by  the  fact  that  they  ferment  inulin 
and  are  soluble  in  bile-salt  solutions. 

Four  chief  strains  have  been  isolated  for  serum 
108 


Respiratory  System. 


manufacture  purposes.  No  doubt  there  are  many 
more. 

Streptococcus, — Streptococci  are  Gram-positive, 
more  or  less  spherical  cocci  which  grow  in  longer  or 
shorter  chains.  They  vary  in  size  from  i  ju,  in 
diameter  to  sometimes  a  quarter  of  that  size,  and  it 
is  quite  common  in  some  strains  to  find  the  chain 
increasing  in  the  size  of  its  elements  from  one  end  to 
the  other,  so  that  at  one  end  the  cocci  may  be  quite 
small,  say  "25  jit  ;  at  the  other  they  may  be  2  /x.  In 
some  strains  the  elements  of  the  chains  tend  to 
become  elongated  into  bacillary  forms. 

The  colonies  are  small  like  those  of  the  pneumo- 
coccus,  but  they  look  slightly  less  translucent.  In 
some  strains  the  colonies  are  very  minute.  Chain 
formation  develops  best  in  broth.  Some  strains 
develop  a  capsule. 

They  vary  enormously  in  toxicity.  By  passage 
through  rabbits  a  strain  has  been  so  increased  in 
virulence  that,  while  at  first  it  took  the  growth  from 
several  agar  slopes  to  kill  the  animal,  after  several 
passages  one  microbe  under  the  skin  of  a  rabbit  was 
certain  death. 

There  are  niany  Gram-negative  cocci  that  infect 
the  respiratory  passages.  The  following  are  the  most 
common  in  catarrhs : — 

Micrococcus,  or  Diplococcus  Catarrhalis. — This 
microbe  is  on  the  average  about  i  /x  in  diameter  and 
usually  occurs  in  pairs,  the  sides  in  apposition  being 
flattened. 

It  grows  vigorously  both  at  37  deg.  C.  and  at  room 
temperature.    The  colonies  attain  a  size  of  2,  3  or 

109 


Therapeutic  Immunisation. 


more  millimetres  in  diameter,  are  heaped  up,  and 
usually  have  a  yellowish  tint.  The  colonies  are  firm 
though  friable,  but  it  is  very  hard  to  get  the  cocci 
separated  from  each  other,  as  they  adhere  in 
masses. 

Another  kind  much  less  common  is  the  Diplococcus 
pharyngis  siccus,  whose  colonies  are  very  tough  and 
adhere  to  the  surface  of  the  medium.  It  actively 
ferments  glucose,  maltose,  saccharose,  and  inulin. 

The  Diplococcus  mucosus  has  slimy  colonies. 

There  are  other  diplococci  which  produce  pigment, 
such  as  the  Micrococcus  flavus. 

Micrococcus  tetragenus  is  fairly  common.  This 
Gram-positive  coccus  commonly  divides  in  two 
plains,  so  that  groups  of  four  arise,  the  elements  of 
which  are  about  i  in  diameter.  The  whole  group 
is  usually  surrounded  by  a  capsule.  It  grows  on 
blood-agar  as  white  colonies,  large  and  tending  to 
spread.  The  colonies  are  very  tenacious  and  viscid 
owing  to  the  gelatinous  nature  of  the  sheaths  of  the 
cocci.  The  M.  paratetragcmts  also  sometimes  occurs  ; 
the  individual  elements  of  the  tetrads  are  quite 
3  or  4  /X  in  diameter. 

Pneumobacillus  of  Friedlander. — This  Gram-nega- 
tive, frequently  capsulated  bacillus  varies  in  size 
from  coccobacillary  forms  to  bacilli  4  or  more 
microns  in  length.  It  is  non-motile.  It  grows  as 
white,  shiny,  viscous  colonies  on  blood-agar.  It 
actively  ferments  most  of  the  sugars  used  in  bac- 
teriological tests.  It  produces  acid  and  gas  in 
glucose,  lactose,  saccharose,  mannite,  dulcite,  adonite, 
sorbite,  inosite  ;    and  produces  acid  in  milk,  but 

no 


Respiratory  System. 


sometimes  no  clot.  It  does  not  liquefy  gelatine. 
It  is,  in  fact,  closely  related  to  the  Bacillus  coli 
group. 

Bacillus  coli, — Members  of  the  group  are  rare  in 
sputum.  They  vary  in  size  from  coccobacilli  to 
bacilli  10  /x  in  length ;  the  average  size  is  2  to  4  /x 
and  about  '5  /x  broad. 

It  is  usually  feebly  motile.  Gram-negative,  and 
grows  as  large,  dense,  greyish-white  colonies. 

It  has  characteristic  fermentation  reactions  on 
sugars,  producing  acid  and  gas  in  glucose,  lactose, 
mannite,  dulcite,  sorbite,  and  acid  and  clot  in  milk. 
It  does  not  liquefy  gelatine. 

Bacillus  pyocyaneus. — Another  uncommon  para- 
site in  the  respiratory  tract. 

B.  pyocyaneus  is  a  small  Gram-negative  motile 
bacillus  1*5  [jl  to  3  /x  in  length  and  less  than  -5  [jl 
in  thickness.  On  ordinary  agar  this  microbe  is 
easily  identified  by  the  development  of  a  green 
pigment. 

Bacillus  influenzce  is  a  tiny  Gram-negative  non- 
motile  bacillus,  usually  not  exceeding  1*5  /x  in  length 
and  '3  jtx  in  thickness,  with  rounded  ends.  It  grows  as 
minute  transparent  colonies  on  blood-agar. 

The  Bacillus  pertussis, — Bordet's  whooping-cough 
bacillus  is  very  similar  to  the  influenza  bacillus  in 
morphology  and  growth. 

Fairly  common  in  sputum  as  well  as  in  pyor- 
rhoea alveolaris  is  a  tiny  Gram-negative  bacillus 
morphologically  like  the  influenza  bacillus,  but 
growing  profusely  on  blood-agar.  That  it  is  patho- 
genic there  can  be  no  doubt,  since  the  sputum  of 

III 


Therapeutic  Immunisation. 


patients  reduced  markedly  on  treatment  with  a 
vaccine  of  it,  and  focal  reactions  occurred. 

Other  larger  Gram-negative  bacilli  occur  which 
need  working  out  and  description. 

Diphtheroid  bacilli. — These  microbes  grow  as 
small,  clear  colonies,  and  in  morphology  resemble  the 
true  diphtheria  bacillus — some  more  and  some  less. 
Diphtheroids  are  quite  common  in  tubercular  sputum 
and  catarrhal  conditions,  and  often  produce  epi- 
demics of  colds. 

There  are,  I  think,  many  varieties  which  need 
working  out  and  description. 

Most  of  these  catarrh-producing  microbes  grow 
best  on  blood-  agar  plates .  The  specimen  for  examina- 
tion can  be  obtained  by  passing  a  platinum  loop 
backwards  through  the  anterior  nares  after  thorough 
cleansing  the  atrium.  It  is  better,  however,  to 
get  the  patient  to  aspirate  the  gobbet  of  sputum 
from  the  nose  and  expectorate  it  into  a  sterile 
bottle.  This  is  washed,  conveniently  in  a  sterile  tea- 
strainer,  in  order  to  get  rid  of  mouth  microbes. 
The  centre  of  the  piece  of  sputum  is  then  spread 
on  the  blood-agar  plate.  A  smear  is  made  from 
the  muco-pus  and  stained  by  Gram's  method,  to 
compare  with  the  microbes  that  grow. 

If  more  than  one  microbe  grows,  as  is  usually 
the  case,  the  microbes  must  be  subcultured  and  a 
vaccine  should  be  made  from  each. 

The  ozaena  bacillus  grows  well  on  blood-agar. 
Other  catarrhal  microbes  are  commonly  present, 
notably  staphylococci,  so  that  a  mixed  vaccine  is 
always  necessary. 

112 


Respiratory  System. 


Prophylaxis :  Treatment. — There  are  two  methods 
of  '  catching  cold  '  :  (i)  The  patient  suffers  from 
a  chronic  infection  and  gets  acute  exacerbations 
when  his  resistance  is  lowered  by  chills  and  other 
causes  of  lowering  his  resistance,  or  (2)  both  this 
class  and  those  who  do  not  suffer  from  chronic 
catarrhs  get  infected  with  virulent  microbes  from 
infected  patients.  The  first  class  are  in  fact  carriers, 
and  their  microbes  become  more  virulent  when 
their  resistance  is  lowered  or  when  they  get  into 
susceptible  individuals.  The  chronic  infections  are, 
as  a  rule,  sequels  to  the  acute,  and  therefore  prophy- 
laxis consists  in  either  treating  the  acute  catarrhs 
with  vaccine  or,  at  any  rate,  doing  so  if  they  do 
not  completely  clear  up.  It  is  not  practicable  to 
inoculate  a  healthy  person  against  all  the  microbes 
that  cause  catarrh.  In  the  case  of  whooping-cough 
epidemics,  prophylactic  inoculation  is  practicable 
and  has  given  good  results.  All  the  contacts  should 
receive  doses  ranging  from  50  to  200  millions, 
according  to  age. 

It  is  remarkable  how  quickly  an  acute  catarrh 
will  clear  up  with  an  autogenous  vaccine. 

The  initial  dose  of  most  of  the  microbes  is  small. 
A  dose  of  2|  million  is  a  usual  one  for  all  except  the 
staphylococci,  when  25  million  may  be  given  ;  the 
usual  sequence  is  2|,  5,  7I,  10,  15,  20,  30,  50,  75,  100, 
and  so  on;  for  staphylococci,  25,  50,  75,  100,  200, 
or  more.  These  acute  catarrhs  usually  clear  up 
with  a  few  injections.  In  chronic  cases  or  when 
the  acute  is  grafted  on  to  the  chronic  it  may  be 
necessary  to  attain  500 — 1,000  million  or  more,  or 

T.I.  J 12  8 


Therapeutic  Immunisation. 


2,000 — 5,000  million  or  more  in  the  case  of  staphy- 
lococci. As  in  other  cases,  the  upper  limit  of  dosage 
must  be  judged  for  each  individual.  The  initial  dose 
may  appear  small,  but  one  frequently  gets  focal  and 
general  reactions  with  it  in  chronic  cases.  The 
intervals  are  usually  one  or  two  days  between  the 
smaller  doses,  gradually  increasing  the  period  as  the 
dose  gets  larger  or  if  there  is  marked  reaction. 
In  acute  cases  it  is  quite  possible  to  have  a  vaccine 
ready  in  twenty-four  hours  or  less  by  omitting  the 
usual  tests  and  making  sure  of  sterility  by  giving  a 
rather  longer  heating  than  usual.  In  such  emergency 
cases  a  vaccine  made  from  the  original  plate  may  be 
used  containing  all  the  microbes  that  grow,  pending 
the  making  of  a  more  accurate  vaccine  from  sub- 
cultures. 

In  the  early  stages  of  whooping-cough  a  pure 
B.  pertussis  vaccine  may  be  used,  but  later  the 
infection  becomes  mixed,  and  therefore  a  mixed 
autogenous  vaccine  becomes  necessary. 

The  treatment  of  empyemata  of  the  accessory 
sinuses  is  the  same  as  for  the  nasal  passages  except 
that  drainage  must  be  produced  by  operation. 

Nasal  obstruction  produced  by  swollen  turbinals 
is  due,  as  we  have  seen,  to  infection,  and  local  treat- 
ment by  cautery  is  generally  useless  as  it  does  not 
remove  the  cause  and  at  best  only  gives  temporary 
relief,  and  removal  of  the  inferior  turbinals  is  most 
harmful,  often  leading  to  '  dry  nose.' 

Adenoids  are  the  result  of  chronic  inflamma- 
tion in  the  naso-pharynx.  If  the  microbe  or  microbes 
that  produce  the  condition  are  not  dealt  with  by 

114 


Respiratory  System. 


inoculation  the  adenoids  frequently  return  after 
removal.  The  microbes  are  those  that  ordinarily 
produce  catarrh. 

No  inflammation  of  the  respiratory  tract  should 
ever,  nor  need  ever,  become  chronic. 

Asthma. — While  there  can  be  no  doubt  that  there 
is  a  neurosis  in  this  condition  it  is  equally  certain 
that  the  hypersensitiveness  of  the  nasal  mucous 
membrane  is  very  frequently,  if  not  always,  pro- 
duced and  kept  up  by  infection  of  it  by  catarrh- 
producing  microbes,  since  it  is  nearly  constantly 
accompanied  by  chronic  nasopharyngitis  and  bron- 
chitis. If  the  vicious  circle  is  broken  by  over- 
coming the  chronic  infection  the  hypersensitiveness 
of  the  mucous  membrane  gradually  subsides.  Great 
care  must  be  exercised  in  immunisation ;  the  initial 
dose  must  be  half  the  usual  one  and  the  dose  very 
gradually  increased,  since  these  cases  are  more 
liable  to  severe  reactions  then  ordinary  cases  of 
bronchitis. 

Hay  Fever. — In  hay  fever  the  attack  is  produced 
by  the  irritation  of  the  nasal  mucous  membrane 
and  conjunctivae  by  pollen  or  dust.  The  condition 
can  frequently  be  cured  by  immunising  the  patient 
to  the  protein  of  various  kinds  of  pollen. 

The  pollen  extract  is  made  by  grinding  up  the 
mixed  pollen  in  normal  saline  containing  0*5  per 
cent,  phenol.  The  initial  dose  is  the  extract  of 
•0001  mg.  of  dry  pollen,  and  the  dose  should  be 
increased  until  one  thousand  times  ('i  mg.)  this 
dose  is  attained.  The  intervals  depend  on  reactions, 
generally  3 — 5  days. 

115 


Therapeutic  Immunisation. 


Tonsillitis  is  an  important  condition,  as  the 
microbes  causing  it  may  produce  inflammations  of 
the  intestinal  tract  and  also  invade  the  blood 
stream  via  the  lymphatics  and  cause  endocarditis, 
rheumatic  fever,  or  the  infection  of  other  tissues. 

Bacteriology, — Many  different  microbes  cause 
tonsillitis.  Undoubtedly  the  most  important  are 
streptococci,  which  are  the  most  common  cause  of 
rheumatic  fever.  Many  others  also  cause  it,  e.g., 
staphylococci,  pneumococci,  M.  catarrhalis.  The 
Bacillus  fusiformis  is  found  in  some  cases  of 
chronic  follicular  tonsillitis  ;  it  is  commonly  found 
associated  with  other  microbes,  notably  streptococci 
and  staphylococci  and  spirilla.  It  is  strictly  anae- 
robic and  grows  best  on  glucose-agar. 

Pathology. — In  acute  tonsillitis  the  gland  is  en- 
larged and  congested,  there  is  hyperplasia  of  the 
lymphoid  elements,  and  there  is  exudation  of  serum 
and  cells  into  the  tissues  and  sometimes  on  the 
surface.  This  exudate  mixed  with  microbes  may  be 
most  marked  in  the  crypts,  and  the  condition  may 
go  on  to  suppuration  in  the  tonsil  itself  or  behind  it, 
producing  a  tonsillar  abscess  or  quinsy. 

Treatment. — If  the  acute  tonsillitis  becomes 
chronic,  or  if  repeated  suppurations  (quinsy)  occur, 
the  condition  should  always  be  treated  by  removal 
of  the  tonsil  and  a  course  of  vaccine.  This  is 
especially  important  in  children  where  tonsiUitis 
caused  by  streptococci  is  the  common  precursor  of 
endocarditis  and  rheumatic  fever. 

The  initial  dose  depends  on  the  microbes  found : 
generally,  2|  milhon  of  streptococci,  25  to  50  million 

116 


Respiratory  System. 


of  staphylococci.  Five  million  will  be  quite  large 
enough  of  B,  fusiformis  to  start  with.  The  series 
of  doses  are  the  same  as  those  given  in  nasal 
infections  {q.v,). 

Lungs. — Inflammation  of  the  lung  parenchyma 
may  be  produced  by  any  or  several  of  the  catarrh- 
producing  microbes  already  mentioned.  In  acute 
bronchitis  affecting  the  smaller  bronchi,  lobules  of 
the  lung  attached  to  inflamed  bronchioles  are  con- 
stantly involved  ;  this  condition  is  known  as 
broncho-pneumonia.  It  is  sometimes  so  extensive 
that  the  inflamed  areas  coalesce,  so  that  the  whole  or 
part  of  a  lobe  may  be  involved.  The  most  common 
cause  of  inflammation  of  the  lung  affecting  the 
whole  lung,  a  lobe  or  a  large  part  of  a  lobe  is  the 
pneumococcus,  either  alone  or  combined  with  other 
of  the  catarrh- producing  microbes.  This  lobar  pneu- 
monia is  really  a  septicaemia  with  focal  manifesta- 
tions in  the  lung.  It  must  not  be  forgotten  that 
the  lungs  are  one  of  the  chief  sites  of  the  phagocy- 
tosis of  microbes  which  are  circulating  in  the  blood. 
They  can  be  infected  via  the  respiratory  passages 
and  also  by  the  lymphatic  channels.  Microbes  of  all 
sorts  are  found  in  healthy  individuals  in  the  mucous 
membrane  down  as  far  as  the  smaller  bronchi,  but 
not  in  the  bronchioles  or  alveoli. 

Lobar  Pneumonia  is  usually  caused  by  the 
pneumococcus  of  Frankel,  less  commonly  by  the 
pneumobacillus  of  Friedlander. 

The  infection  may  take  place  through  the  respira- 
tory passages  or  through  the  blood  stream.  The 
pneumococcus  may  be  inhabiting  the  mouth  or 

117 


Therapeutic  Immunisation. 


upper  respiratory  passages,  or  the  infection  may  come 
from  without.  The  blood  infection  may  come  from 
pyorrhoea  alveolaris  or  the  tonsils.  If  the  microbes 
are  aspirated  into  the  bronchi  they  may  be  carried 
by  leucocytes  into  the  lymphatic  glands  at  the  hilus. 
They  may  cause  inflammation  here  of  the  glands 
draining  a  lobe  or  part  of  a  lobe,  obstructing  the 
lymph  flow  from  that  area ;  this  leads  to  reversal  of 
the  lymph  stream  and  the  carrying  outwards  of  the 
infection  along  the  lymphatics  of  that  area.  These 
may  reach  the  pleura,  infect  it  and  be  carried 
inwards  by  the  lymphatics  of  other  areas.  When 
the  blood  stream  is  first  infected  it  is  a  little  difficult 
to  understand  what  determines  the  inflammation  of 
a  particular  area  of  the  lung.  Probably  a  lowering  of 
the  resistance  of  that  area,  produced  among  other 
ways  (i)  through  the  nervous  sj^stem  by  chilling  of 
the  skin  over  it  or  by  injury  ;  (2)  interference  with 
its  nutrition  by  previous  interference  with  its 
lymph  circulation  by  infection,  for  instance,  with  the 
tubercle  bacillus  ;  (3)  or  it  may  be  at  the  time  being 
attacked  by  other  microbes  so  that  the  infection  is, 
as  it  commonly  is,  mixed. 

Pathology. — The  alveolar  capillaries  become  dis- 
tended and  tortuous,  the  alveoli  then  become  filled 
with  plasma  containing  red  corpuscles,  leucocytes 
and  alveolar  cells  which  have  desquamated  from 
the  alveolar  walls  or  have  become  budded  off ; 
the  plasma  clots,  so  that  the  cells  are  enmeshed  in 
a  fibrin  network.  Fibrino-cellular  plugs  block  the 
alveolar  and  lymphatic  capillaries,  and  there  is  a 
sero-cellular  exudate  into  the  interlobular  connective 

118 


Respiratory  System. 


tissue.  There  is  always  inflammation  of  the  over- 
lying pleura,  unless  the  pneumonia  does  not  reach 
the  surface,  with  a  deposit  of  fibrin  on  it.  There  is 
acute  inflammation  of  the  bronchi  of  the  part.  The 
red  cells  are  gradually  phagocytosed  by  leucocytes 
and  other  cells,  so  that  the  lung  looks  grey  instead 
of  red.  If  the  patient  survives  and  recovery  is 
normal  the  fibrin .  blocking  the  alveoli  and  capil- 
laries becomes  phagocytosed  or  digested  by  tryptic 
ferments ;  the  phagocytic  cells  which  are  effete 
undergo  fatty  degeneration  and  autolysis  and  the 
softened  exudate  is  removed  via  the  lymphatics,  or 
comes  away  via  the  bronchi. 

If  resolution  does  not  take  place  the  fibrino- 
cellular  clot  in  the  lung  tissue  may  become  organised, 
just  as  a  blood  clot  does,  fibrosis  resulting.  Or  it 
may  be  invaded  by  other  microbes,  which  may  have 
been  present  from  the  first,  for  instance,  the  tubercle 
bacillus  with  subsequent  caseation,  or  pyogenic 
microbes  which  may  cause  abscess  or  grangrene. 

The  causative  microbe  can  be  isolated  from  the 
sputum,  from  the  blood  or  from  lung  by  puncture. 
The  latter  is  a  very  rapid  and  effective  way  and 
appears  to  be  perfectly  safe.  A  syringe  with  i  c.c. 
of  sterile  broth  or  normal  saline  and  a  long  No.  7 
needle  attached  is  plunged  into  the  solid  lung,  a 
little  of  the  fluid  is  injected  and  aspirated  back  into 
the  syringe  and  from  it  cultures  are  made.  If  the 
cultures  are  made  from  the  sputum,  mouth  microbes 
should  be  first  washed  away  from  it  with  sterile 
water  and  the  central  part  of  the  sputum  used.  To 
isolate  from  the  blood  10  c.c.  of  blood  should  be 


119 


Therapeutic  Immunisation. 


taken  from  a  vein  in  the  anticubital  fossa  and  put 
in  100  c.c.  of  broth.  At  the  same  time  some  blood 
should  be  taken  to  add  to  the  agar  medium  on  which 
the  microbe  is  to  be  grown. 

The  material  should  be  sown  thickly  on  the  plate 
so  that  a  vaccine  can  be  made  from  the  first  plate, 
as  the  vaccine  must  be  available  in  as  short  a  time  as 
possible,  subcultures  being  first  made  for  diagnostic 
purposes  so  that  pure  vaccines  can  be  made  if 
more  than  one  microbe  grows.  The  pneumococcus 
can  be  distinguished  from  other  members  of  the 
streptococcal  group  by  its  solution  in  bile  salts 
and  less  certainly  by  its  fermentation  of  inulin. 

Friedlander's  pneumobacillus  has  quite  charac- 
teristic sugar  reactions. 

There  are,  of  course,  many  strains  of  the  pneumo- 
coccus. At  the  Rockefeller  Institute  pneumococci 
are  divided  into  four  groups.  Antisera  produced  for 
any  one  group  will  not  agglutinate  a  microbe  from 
any  other  group  nor,  in  vivo,  neutralise  their  toxins. 

The  toxin  of  the  pneumococcus  is  an  endotoxin, 
the  microbe  producing  no  soluble  toxin  in  vitro. 
The  filtered  blood  of  animals  dying  of  the  infection 
and  of  patients  before  the  crisis  is  toxic,  so  that  in 
the  body  an  exotoxin  may  be  formed.  Of  course 
this  toxicity  of  the  blood  may  be  due  to  lysis  of  the 
microbe  with  liberation  of  endotoxin.  Before  the 
crisis  the  amount  of  complement  and  the  opsonic 
power  of  the  patient's  serum  is  low;  both  rise 
abruptly  immediately  before  it.  Small  amounts  of 
specific  antibodies  are  formed.  Immunity  appears  to 
depend  practically  entirely  on  efiicient  phagocytosis. 

120 


Respiratory  System. 


Prophylaxis, — If  the  patient  has  had  a  previous 
attack  of  pneumonia  which  has  not  been  treated 
with  vaccine  his  resistance  to  the  microbe  ought  to 
be  increased  by  a  course  of  autogenous  vaccine,  as 
repeated  attacks  are  common.  Any  focus  of  infec- 
tion, e.g,,  post-nasal  catarrh  or  pyorrhoea  alveolaris, 
ought  never  to  be  allowed  to  continue. 

Treatment, — To  judge  of  the  results  of  any  form 
of  treatment  in  pneumonia  requires  very  large 
figures,  since  the  death  rate  varies  so  much  with  the 
virulence  of  the  infecting  microbe  and  the  reactivity 
of  the  patient.  Spontaneous  recovery  in  a  few  days 
is  quite  common  without  any  form  of  treatment. 
The  mortality  of  the  disease,  however,  is  so  very  high 
that  a  great  deal  more  than  expectant  treatment  is 
desirable. 

Many  polyvalent  sera  are  obtainable  and  should 
always  be  used  on  the  chance  that  the  particular 
one  used  may  contain  antibodies  appropriate  for  the 
strain  infecting  the  patient.  If  it  does  not  it  is 
useless,  but  does  no  harm. 

The  same  considerations  apply  to  stock  vaccines. 
They  must  be  polyvalent,  and,  since  most  com- 
mercial pneumococcic  vaccines  are  of  feeble  potency 
a  comparatively  large  dose,  25^ — 50  millions,  must 
be  given.  Serum  and  vaccine  should  be  given 
simultaneously  so  as  to  produce  a  mixed  immunity. 
As  soon  as  possible  an  autogenous  vaccine  must  be 
available.  The  method  of  obtaining  the  specimen 
and  the  most  suitable  medium  have  already  been 
referred  to.  Heating  for  fifteen  minutes  at  58  deg.  C. 
is  quite  sufficient  to  kill  the  microbe.    The  initial 

121 


Therapeutic  Immunisation. 


dose  is  2j  million  and  the  sequence  2j,  5,  7J,  10,  15, 
20.  The  rules  laid  down  for  the  giving  of  vaccines 
in  acute  cases  must  be  followed.  I  have  no  doubt 
that  there  is  a  great  future  for  intravenous  chemo- 
therapy in  this  and  other  acute  infectious  diseases. 
Especially  is  this  so  in  pneumonia,  where  the  focal 
lesion  is  in  the  lungs.  I  have  not  yet  had  an  oppor- 
tunity of  using  the  sodium  salt  of  di-iodosalicylic  acid 
in  pneumonia,  but  its  rapid  effect  in  streptococcal 
infections,  including  those  of  the  lungs,  is  such  that 

1  am  very  hopeful  of  its  future  in  this  disease; 

2  to  5  c.c.  of  a  I  per  cent,  solution,  according  to  age, 
is  the  dose  indicated.  It  should  be  given  every 
twenty-four  hours.  If  possible  the  clotting  of  the 
blood  in  the  capillaries  and  alveoli  should  be  pre- 
vented. The  best  way  we  have  of  doing  this  is  by 
giving  sodium  citrate  i  gramme  (gr.  xv.)  every  four 
hours.  Ethylhydrocuprein  has  given  very  dis- 
appointing results. 

Broncho-pneumonia. — The  etiology  and  treat- 
ment of  broncho-pneumonia  is  the  same  as  that  of 
acute  bronchitis  and  need  not  be  considered 
separately. 

Pleurisy. — The  pleura  is  always  infected  when 
the  underlying  lung  is,  and  the  cause  is,  of  course,  the 
same,  viz.,  the  various  catarrh-producing  microbes. 
By  far  the  most  common  cause  of  pleurisy  with 
effusion  is  the  tubercle  bacillus. 

Pathology, — When  infected  the  pleura  becomes 
hyperaemic  and  there  is  an  increased  exudation  of 
lymph  from  the  capillaries  ;  this  lymph  contains 
more  fibrin  than  normally.    The  surface  becomes 

122 


Respiratory  System. 


roughened  owing  to  the  endotheKal  cells  becoming 
cuboidal  and  budding  off  or  desquamating,  fibrin 
becoming  deposited  on  the  surface.  The  stomata 
become  plugged  with  fibrin.  If,  then,  there  is  a  con- 
tinued exudation  of  lymph  it  cannot  escape  and  an 
effusion  results.  If  the  causative  microbes  attract 
large  numbers  of  leucocytes  and  kill  them  an 
empyema  results.  The  fibrinous  deposit  frequently 
becomes  organised  and  adhesions  result.  If  the  toxin 
of  the  microbe  produces  lysis  of  the  endothelial  cells 
of  the  capillaries  the  effusion  is  haemorrhagic. 

Diagnosis, — When  the  pleurisy  is  connected  with 
lung  lesion  or  occurs  in  the  course  of  an  acute 
catarrh  the  cause  may  be  presumed  to  be  that  of  the 
lung  lesion. 

Pleurisy  with  effusion  is  most  commonly  tuber- 
cular, but  sometimes  it  is  not,  so  that  it  is  always 
well  to  make  an  ordinary  bacteriological  examina- 
tion. The  fluid  should  be  drawn  off  into  a  sterile 
vessel  and  allowed  to  clot ;  the  clot  is  removed  and 
digested  with  liquor  pancreaticus,  centrifuged,  and 
cultures  made  from  the  deposit,  which  should  also 
be  stained  for  tubercle  bacilli. 

If  no  microbes  grow  and  no  tubercle  bacilli  are 
seen  the  patient  should  certainly  be  tested  for 
tuberculosis  by  subcutaneous  injections  of  tuber- 
culin (see  p.  215). 

When  there  is  an  empyema  there  is  no  difficulty, 
as  a  rule,  in  isolating  the  microbe  from  the  pus.  The 
most  common  causes  are  pneumococci,  streptococci, 
or  staphylococci;  but  any  microbe  almost  can 
produce  it,  for  instance,  B,  coli,  B.  typhosus,  or 

123 


Therapeutic  Immunisation. 


the  paratyphoids.  In  the  entericas,  however,  the 
empyema  is  often  not  caused  by  the  primary  infec- 
tion, but  by  other  microbes. 

Treatment, — When  the  pleurisy  is  connected  with 
a  lung  lesion  the  treatment  is  that  of  the  lung 
lesion.  Sometimes  dry  pleurisy  occurs  with  no 
obvious  lung  lesion  in  rheumatic  conditions.  There 
is  then  a  focus  of  infection  somewhere  as  in  the  gums, 
from  which  the  causative  microbe,  usually  but  not 
always  streptococci,  can  be  procured. 

If  microbes  other  than  the  tubercle  bacillus  are 
found  in  a  pleurisy  with  effusion,  vaccines  are  made 
from  them  and  an  ascending  series  of  doses  given. 
A  very  useful  adjuvant  treatment  is  to  inject  5  to 
10  c.c.  of  the  effused  fluid,  taken  from  the  chest, 
underneath  the  skin  every  few  days. 

An  empyema  (non-tubercular)  must  be  drained 
as  soon  as  possible  and  an  ascending  series  of  doses 
of  a  vaccine  from  the  causative  microbe  given. 
The  initial  dose  is  2|  million  for  all  microbes  except 
the  staphylococcus,  where  it  is  25  million,  the  series 
is  2|,  5,  7J,  10,  15,  20,  etc.,  up  to  at  least  500,  while 
in  the  case  of  staphylococci  it  is  25,  50,  100,  150,  200, 
and  so  on,  up  to  at  least  2,000. 


124 


CHAPTER  VIII. 


URINO-GENITAL  SYSTEM. 

Nephritis. — Except  in  the  case  of  acute  pyogenic 
infections  the  cause  of  inflammations  of  the  kidneys 
which  do  not  produce  pus  in  the  urine  (acute  and 
chronic  Bright 's  disease)  is  not  properly  understood ; 
indeed,  as  far  as  I  know,  httle  or  no  attempt  has 
been  made  to  investigate  them  bacteriologically. 

The  kidneys  may  be  infected  through  the  blood 
stream,  probably  much  the  most  common  way,  or 
they  may  be  infected  by  pyogenic  organisms 
ascending  along  the  ureter.  In  either  case  the  pelvis 
of  the  kidney  may  be  involved  as  well,  a  pyelo- 
nephritis resulting. 

Acute  and  Sub-acute  Non-suppurative 
Nephritis  (Bright's  Disease).  —  In  most  fevers 
the  kidneys  are  more  or  less  affected.  This  is  not 
surprising  since  excretion  of  microbes  by  the  kidneys 
is  one  of  the  chief  methods  of  getting  rid  of  microbes 
in  the  circulation. 

In  scarlet  fever  the  kidneys  are  commonly  in- 
fected by  way  of  the  blood  stream,  the  cause 
probably  always  being  streptococci.  I  have  seen 
many  cases  of  a  similar  kind  associated  with  acute 
tonsillitis.  They  also  may  become  infected  as  a 
sequel  to  pneumonia  and  similar  infections.  So  also 

125 


Therapeutic  Immunisation. 


in  the  typhoid  and  the  paratyphoid  infections  the 
kidneys  may  become  acutely  infected. 

I  have  made  bacteriological  investigation  of  a  few 
cases  of  sub-acute  nephritis  in  soldiers  and  found 
various  microbes  (see  p.  130).  These  microbes  were 
found  on  several  examinations  ;  both  focal  and 
general  reactions  occurred  on  giving  the  patient 
vaccines  made  from  them  ;  and  in  most  cases  the 
albumen  entirely  disappeared  from  the  urine  or  was 
reduced  to  a  trace.  I  have  little  doubt  that  I  was 
using  the  causative  organisms. 

No  causative  organism  has  been  isolated  from 
acute  trench  nephritis. 

Amte  suppurative  nephritis  occurs  in  the  course  of 
pyaemias  and  septicaemias  with  pyogenic  microbes 
and  as  an  extension  of  a  suppurative  pyelitis. 

Chronic  nephritis  may  be  a  sequel  to  the  acute 
condition,  or  may  come  on  so  sub-acutely  as  to  be 
chronic  from  the  beginning.  As  I  have  said,  their 
origin  is  quite  obscure.  I  have  little  doubt  that 
many  of  them  will  be  found  to  be  microbial  in 
origin,  for  the  more  one  examines  bacteriologically 
the  urine  of  patients  suffering  from  chronic  rheu- 
matism and  such  conditions,  the  more  one  realises 
the  number  of  people  who  are  excreting  microbes 
in  their  urine  without  any  trace  of  pus  cells  or 
albumen  in  the  urine.  It  seems  to  me  improbable 
that  the  kidneys  in  a  certain  number  of  such  cases 
will  not  become  affected  sooner  or  later,  especially 
as  their  resistance  may  be  lowered  by  excretion 
of  products  of  abnormal  metabolism  (see  p.  154), 
which  they  may  have  to  excrete.    These  abnormal 

126 


Urino-Genital  System. 


metabolic  substances  may  act  on  the  blood-vessels 
primarily  and,  by  affecting  the  nutrition  of  the  cells, 
bring  about  their  degeneration.  As  I  have  already 
stated,  it  is  not  difficult  to  find  sources  of  chronic 
septicaemia,  chronic  pyorrhoea  alveolaris,  tonsillitis 
and  gastroenteritis  being  common  sources. 

The  whole  subject  needs  careful  and  prolonged 
bacteriological  and  other  investigations. 

Pathology.  —  The  cellular  changes  depend  on 
whether  the  glomeruli,  tubules,  interstitial  tissue 
or  blood-vessels  are  primarily  affected,  the  viru- 
lence of  the  causative  microbe,  and  whether  it  is 
pyogenic  or  not. 

In  acute  scarlet  fever  nephritis  the  first  changes 
appear  in  the  glomeruli,  the  endothelial  cells  of  the 
capillaries  of  the  tuft  are  affected  and  red  blood 
corpuscles  escape  into  the  glomerular  space.  The 
endothelial  cells  of  the  capillaries  become  swollen 
and  cuboidal,  and  a  similar  change  of  these  cells  in 
the  arterioles  leads  to  narrowing  of  their  lumen  ; 
these  endothelial  cells  of  the  arterioles  proliferate, 
and  there  is  proliferation  of  the  cells  of  the  glome- 
rular capsule.  The  walls  of  the  arterioles  and  of  the 
glomeruli  become  invaded  with  leucocytes.  The 
result  of  these  changes  is  that  the  circulation  in 
the  glomeruli  ceases  and  there  is  no  excretion  by 
the  glomeruli,  consequently  the  tubules  normally 
flushed  by  the  fluid  secreted  by  the  glomeruli  are 
not  flushed.  Partly  owing  to  this  and  partly  owing 
to  the  action  of  the  toxin,  cloudy  swelling,  degenera- 
tion, desquamation,  and  even  necrosis  of  the  cells 
of  th^  tubules  result.    The  interstitial  tissue  also 


127 


Therapeutic  Immunisation. 


becomes  more  or  less  affected.  As  a  rule,  all  the 
glomeruli  are  not  affected.  If  they  are,  complete  or 
nearly  complete  suppression  of  urine  results. 

In  acute  parenchymatous  nephritis  the  onus  falls 
on  the  tubules,  the  cells  of  which  undergo  cloudy 
swelling  and  proliferation  or,  if  the  toxin  is  powerful, 
necrosis.  Desquamation  follows,  and  the  tubule 
becomes  filled  with  degenerating  or  degenerated 
cells,  cell  debris,  fibrin  and  blood  cells.  The  changes 
in  the  glomeruli  are  slighter,  but  there  is  usually 
oedema  or  congestion  of  the  interstitial  tissue. 

In  acute  interstitial  nephritis  the  first  changes 
are  in  the  interstitial  tissue.  There  is  infiltration  of 
this  tissue  with  lymphocytes,  polynuclear  leuco- 
cytes and  plasma  cells,  especially  between  the 
tubules  of  the  cortex  and  round  the  stellate  and 
interlobular  veins. 

From  the  acute  stage,  if  the  patient  survives, 
the  condition  either  completely  clears  up  or 
passes  through  a  sub-acute  to  the  chronic  stage. 
Fibrous  tissue  forms,  which  contracts  and  leads  to 
various  appearances  according  to  its  extent  and 
position. 

Abscess  is  either  produced  by  a  septic  embolus  in 
pyaemia  or  by  an  ascending  infection  from  the  renal 
pelvis.  In  pyaemia  the  embolus  lodges  in  the  inter- 
lobular arteries,  arterioles  or  capillaries,  and  abscesses 
form  round  them.  The  microbes  later  infect  the 
tubules  through  which  some  of  them  are  being 
excreted,  and  the  pelvis  of  the  kidney  as  a  rule 
becomes  infected.  If  the  primary  infection  is  in  the 
pelvis  the  inflammation  spreads  up  along  the  col- 

128 


Urino-Genital  System. 


lecting  tubules,  elongated  abscesses  being  formed. 
In  both  conditions  the  whole  kidney  is  more  or  less 
affected,  the  interstitial  tissue  showing  oedema, 
congestion  and  infiltration  with  inflammatory  cells. 
Further,  if  the  patient  survives,  the  inflammation 
may  spread  to  the  surrounding  tissues  and  a 
perinephritic  abscess  result ;  pyelitis  and  ureteritis 
may  result  either  from  infection  from  above,  due  to 
microbes  excreted  from  the  kidney  or  from  below 
by  infections  ascending  from  the  bladder.  They  are 
often  complicated  or  originated  by  the  presence  of 
a  calculus. 

Bacteriology. — The  diagnosis  of  the  kind  of  infec- 
tion and  the  settling  of  the  question  as  to  whether 
one  or  both  kidneys  are  affected  require  some  care, 
since  in  one-sided  cases  the  symptoms  may  be 
referred  to  the  opposite  side  to  the  one  affected. 
Cystoscopy  and  catheterisation  of  the  ureters 
must  be  resorted  to  in  such  cases. 

Great  care  must  be  taken  in  taking  the  specimens 
for  bacteriological  investigation.  In  the  male, 
either  a  catheter  can  be  used,  or  the  specimen  may 
be  passed  directly  into  a  sterile  vessel,  the  whole 
glans  penis  being  thoroughly  disinfected  first.  The 
first  half  ounce  of  urine  passed  should  be  rejected. 

In  the  female,  a  catheter  must  be  used  and  the 
external  genitaUa  and  the  meatus  most  carefully 
cleansed  and  disinfected  before  passing  it.  Thorough 
douching  in  a  proper  gynecological  chair  is  desirable. 

The  diagnosis  should  be  checked  by  several 
examinations.  In  the  later  stages  of  chronic  neph- 
ritis it  is  improbable,  in  most  cases,  that  the  original 

T.I.  129  9 


Therapeutic  Immunisation. 

causative  organism  will  be  present  so  that  it  is  of 
the  utmost  importance  to  examine  these  cases  in 
the  early  stages.  There  is,  as  a  rule,  no  difficulty 
in  identifying  the  causative  microbe  or  microbes. 
The  acute  glomerular  nephritis  which  occurs  in 
scarlet  fever  and  after  acute  sore  throats  is  probably 
alwaj^s  caused  by  streptococci.  Some  cases  of  acute 
and  sub-acute  parenchymatous  nephritis  I  investi- 
gated were  caused  by  Staphylococcus  aureus  (one 
case),  Staphylococcus  albus  (two  cases).  Gram-posi- 
tive bacilli  (two  cases)  ;  a  Gram-negative  bacillus, 
non-motile,  producing  acid  in  litmus  milk  but  not 
affecting  the  ordinary  sugar  media  nor  producing 
liquefaction  of  gelatine.  The  acute  descending 
pyelonephritis  is  usually  staphylococcal,  strepto- 
coccal or  produced  by  members  of  the  typhoid-coli 
group.  Quite  commonly  B,  coli  is  associated  with 
the  typhoid  or  one  of  the  paratyphoids  in  post- 
typhoidal  inflammation,  while  B,  coli  and  staphy- 
lococci may  be  associated. 

In  ascending  inflammation  the  infection  is  most 
commonly  produced  by  the  B.  coli,  very  rarely  by 
gonococci. 

Prophylaxis  and  Treatment. — The  treatment  of 
scarlet  fever  and  acute  streptococcal  infections  of 
throats  by  immediate  use  of  antisera  and  the  inocula- 
tion of  an  autogenous  vaccine  as  soon  as  possible 
will  certainly  reduce  the  number  of  cases  of  acute 
nephritis.  Failing  these  the  exhibition  of  sali- 
cylates is  certainly  better  than  nothing. 

If  localised  infections,  such  as  pyorrhoea  alveo- 
laris,  tonsillitis  and  gastroenteritis,  are  the  source  of 

130 


Urino-Genital  System. 


infection  in  some  of  the  cases  of  acute  and  chronic 
nephritis,  prophylaxis  consists  in  clearing  up  these 
infections  with  vaccines  before  chronic  septicsemia 
occurs. 

The  prophylaxis  of  ascending  infections  consists 
in  treating  the  infection  of  the  lower  urinary 
passages  with  vaccines  so  as  to  prevent  the  spreading 
of  the  infection. 

Acute  streptococcal  nephritis  should  be  treated 
by  the  immediate  injection  of  efficient  polyvalent 
antistreptococcal  serum,  pending  the  isolation  of 
the  causative  microbe  from  the  urine  and  the  making 
of  the  vaccine.  The  doses  should  be  2|-,  5,  7I,  10, 
15,  20  million,  and  larger  if  necessary,  the  intervals 
depending  on  reactions.  The  initial  doses  and  series 
of  all  other  causative  microbes  are  the  same  except 
in  the  case  of  staphylococci,  when  the  doses  are  ten 
times  larger,  viz.,  25,  50,  75,  100, 150,  200,  and  so  on. 
As  in  other  cases  the  more  chronic  the  condition  the 
larger  the  dose  that  will  have  to  be  attained.  When 
the  infection  is  a  double  one,  as  it  quite  commonly 
is — for  instance,  when  B.  coli  is  associated  with  the 
typhoid  or  paratyphoid  bacilli — then  the  initial 
dose  is  2|  +  and  the  series  as  before,  or  if 
staphylococci  and  one  of  the  others  25  +  2|.  Such 
were  the  doses  I  used  with  the  Gram-positive  and 
Gram-negative  bacilli  mentioned  above.  These 
microbes  were  isolated  several  times  from  care- 
fully collected  specimens,  and  vaccines  of  them 
produced  general  and  focal  reactions  in  the  patients. 
After  the  second  dose  (5  miUion)  in  one  of  the  cases 
excreting  the  Gram-negative  bacillus,  the  albumen 

131  9-2 


Therapeutic  Immunisation. 


entirely  disappeared  from  the  urine.  In  chronic 
cases  very  high  doses  may  have  to  be  reached  ;  the 
final  dose  in  a  case  of  double  acute  pyelonephritis 
caused  by  the  B.  coli  was  i,ooo  million. 

In  ascending  pyelonephritis  with  abscess  and  in 
cases  of  perirenal  abscess  the  pus  must  be  evacuated 
through  the  loin,  and  in  calculus  pyelonephritis  or 
pyelitis  the  stone  must  be  removed. 

Vaccines  will  help  the  surgeon  to  save  many 
kidneys  which  otherwise  would  have  to  be  removed. 

The  urine  must  always  be  kept  neutral,  when  acid, 
by  the  exhibition  sodium  citrate,  i  gramme  (15  grains) 
three  or  four  times  a  day  is  usually  about  right. 

Cystitis  is  caused  by  infection  coming  either 
by  way  of  the  ureters  or  urethra,  so  that  it  may 
occur  during  urethritis,  prostatitis  or  pyelonephritis. 
It  is  a  very  common  occurrence  during  '  catheter 
life  '  where  decomposition  of  residual  urine  is  a 
potent  predisposing  cause. 

By  far  the  most  common  cause  is  B.  coli,  but 
many  other  microbes  occur,  typhoid  and  the 
paratyphoids  A  and  B,  staphylococci,  streptococci, 
gonococci,  and  various  microbes  producing  decom- 
position of  urine. 

Pathology. — In  acute  catarrhal  cystitis  the  mucous 
membrane  is  congested  with  red  points,  due  to 
congested  vessels  and  haemorrhages  ;  the  epithelium 
is  swollen  and  desquamating.  The  mucous  mem- 
brane is  infiltrated  with  leucocytes  which  make 
their  way  to  the  surface  and  into  the  urine.  In 
chronic  catarrhal  cystitis  the  bladder  wall  becomes 
thickened,  owing  to  infiltration  of  the  submucous 

132 


Urino-Genital  System. 


coat  as  well,  with  inflammatory  cells,  while,  if  there 
is  obstruction  to  the  outflow  of  urine  there  is  hyper- 
trophy of  the  muscular  walls  with  increase  of 
fibrous  tissue  between  the  muscle  bundles.  If 
the  inflammation  is  very  intense  it  may  lead  to 
superficial  necrosis  forming  a  necrotic  membrane. 
This  may  be  localised  and  cast  off,  an  ulcer  resulting. 
In  very  severe  cases  the  inflammation  may  spread 
to  the  surrounding  tissues. 

Treatment. — Acute  cystitis  yields  very  rapidly  to 
vaccines.  In  chronic  cystitis  it  is  necessary  to 
work  up  to  a  very  big  dose,  as  a  rule ;  this  is  not 
surprising,  considering  the  anatomical  changes  just 
described.  If  the  prostate  is  enlarged  it  is  much 
better  to  have  it  removed. 

The  dosage  of  vaccine  is  the  same  as  for  other 
parts  of  the  urino- genital  system.  The  initial 
dose  of  staphylococcus  may  be  loo  million  unless 
the  kidneys  are  involved,  when  it  must  be  25 
million,  B.  coli  2|  million,  streptococci  2\  million, 
typhoid  and  paratyphoids  2|  million,  gonococcus 
2-|  million.  In  acute  cystitis,  when  a  dose  of  500 
million  staphylococci  and  100  million  of  the  other 
microbes  is  reached  the  patient  is  usually  well. 
As  already  mentioned,  in  chronic  cystitis  very  large 
doses  may  have  to  be  reached.  In  these  cases  lavage 
with  hypertonic  saline  solution  is  very  useful.  As 
in  other  conditions  a  stitch  in  time  saves  nine; 
bladder  infections  ought  not  to  be  allowed  to 
become  chronic. 

If  the  urine  is  acid  it  must  be  kept  neutral  with 
citrate  of  soda. 


133 


Therapeutic  Immunisation. 


Urethritis  in  Male. — Urethritis  in  the  male  is, 
for  all  practical  purposes,  the  result  of  infection 
from  a  vagina  infected  with  the  gonococcus.  Cases 
occasionally  occur  in  which  the  original  infection 
is  some  other  microbe,  but  as  a  rule  the  male  urethra 
seems  able  to  resist  infection  by  other  microbes 
until  its  resistance  is  lowered  by  infection  with  the 
gonococcus. 

Pathology. — The  inflammation  may  be  confined 
to  the  anterior  urethra  or  may  spread  back  to  the 
posterior  urethra  and  infect  the  prostate,  vesiculae 
seminales,  epididymis  and  testis.  It  rarely  spreads 
to  the  bladder.  It  may  get  into  the  circulation 
through  an  ulcer  and  produce  gonorrhoeal  rheumatism 
or  endocarditis  and  septicaemia. 

The  pathological  changes  in  the  urethra  are  those 
of  inflammation,  viz.,  hyperaemia,  infiltration  with 
leucocytes  and  pus  formation.  Ulceration  pro- 
duced by  sloughing  of  the  mucous  membrane  is 
common. 

The  changes  in  the  prostate  may  amount  to  simple 
catarrh  of  the  tubules  with  desquamation  of  their 
cells  and  infiltration  with  leucocytes.  As  a  rule  the 
inflammation  spreads  to  the  interstitial  tissues, 
which  become  infiltrated  with  inflammatory  cells. 
The  prostate  on  examination  may  be  uniformly 
enlarged  and  boggy  if  the  inflammation  is  catarrhal, 
but  if  the  interstitial  tissue  is  infected  the  whole 
gland,  one  lobe  or  parts  of  lobes  are  hard  and 
nodular  and  very  tender. 

These  conditions  if  not  suitably  treated  may  last 
for  months  or  many  years.   Areas  may  break  down 

134 


Urino-Genital  System. 


to  form  abscesses  which  may  be  so  extensive  as  to 
involve  the  whole  gland. 

The  tubules  of  the  epididymis  and  testis  show 
catarrhal  changes  and  are  invaded  with  leucocytes. 
The  tubules  may  dilate  and  form  abscesses,  the 
interstitial  tissue  being  involved  and  the  abscesses 
may  burst  on  the  surface.  More  frequently  under 
suitable  treatment  resolution  occurs.  The  tunica 
vaginalis  is  always  involved  in  epididymitis  and 
usually  in  orchitis. 

Bacteriology. — The  diagnosis  of  gonorrhoea  is  not 
difficult  in  the  acute  stages.  Smears  of  the  purulent 
discharge  from  the  urethra  show  Gram-negative 
diplococci  ingested  in  leucocytes  and  desquamated 
epithelial  cells.  Such  appearances  are  for  all 
practical  purposes  diagnostic. 

Cultures  must  be  made.  The  gonococcus  is  a  very 
delicate  micro-organism  and  requires  special  culture 
medium,  which  must  be  warmed  to  body  tempera- 
ture before  insemination  ;  +  6  agar  with  i  c.c.  of 
human  blood  to  every  lo  c.c.  of  agar  grows  the 
microbe  excellently.  The  agar  must  be  accurately 
+  6  ;  must  be  made  with  fresh  meat  extract,  and 
must  not  have  been  heated  to  more  than  lOO  deg.  C. 
in  its  preparation.  On  this  colonies  of  the  gono- 
coccus grow  to  as  much  as  i  mm.  in  diameter  at 
the  end  of  twenty-four  hours.  They  are  slightly 
milky  in  appearance  and  have  a  clean-cut  contour. 
The  colonies  increase  in  size  for  several  days  until 
they  are  several  millimetres  or  more  in  diameter 
with  a  characteristic  irregular  outline.  They  should 
be  subcultured  not  later  than  three  or  four  days, 

135 


Therapeutic  Immunisation. 


as  the  microbes  in  the  primary  culture  die  out,  as  a 
rule,  towards  the  end  of  a  week. 

For  making  the  blood  agar  the  patient's  own  blood 
may  be  conveniently  used.  It  is  taken  with  a  syringe 
from  one  of  the  veins  in  the  anticubital  fossa,  the 
agar  being  melted  and  cooled  down  to  50  deg.  C. 
before  adding  the  blood ;  one  plate  and  several  slopes 
for  subculture  should  be  made  for  each  patient. 

The  gonococcus  is  a  Gram-negative  diplococcus 
with  the  contiguous  sides  slightly  hollowed  out,  so 
that  each  element  is  somewhat  kidney  shaped.  It 
keeps  its  shape  fairly  well  on  subculture  if  the 
medium  is  suitable  {e.g.,  if  there  is  sufficient  blood 
present).  After  several  subcultures,  as  a  rule, 
pleomorphism  occurs,  small  and  large  round  cocci 
appearing  and  the  diplococcal  form  disappearing.  If 
the  urethritis  becomes  chronic  and  spreads  up  to  the 
posterior  urethra  other  microbes  constantly  invade 
it  and  take  part  in  and  continue  the  condition,  while 
the  gonococcus  frequently  entirely  disappears  from 
the  smears.  There  may  be  one  or  more  of  these 
secondary  invaders.  The  most  common  are  haemo- 
ly tic  and  non-haemolytic  staphylococci ;  diphtheroids, 
of  these  there  are  two  chief  kinds,  one  forming  very 
large  pinkish,  clear  cut,  round  colonies  on  blood 
agar,  the  other  small  translucent  or  very  shghtly 
opaque  colonies  like  those  of  the  diphtheria  bacillus  ; 
streptococci  and  Gram-negative  bacilli  of  several 
kinds.  Some  of  the  latter  give  the  sugar  reactions  of 
coliform  bacilli;  others  do  not  affect  the  ordinary 
sugars  at  all,  and  are  not  motile.  The  Gram-negative 
bacilli  infecting  the  urethra  need  working  out. 

136 


Urino-Genital  System. 


To  take  cultures  the  end  of  the  penis  must  be 
disinfected  with  ether,  the  patient  then  opens  the 
meatus  by  puUing  the  hps  sideways  on  each 
side  and  the  loopful  of  pus  is  removed.  If  the 
prostate  is  involved  it  must  be  massaged  first 
through  the  rectum  so  as  to  get  a  fresh  discharge. 

The  toxin  of  the  gonococcus  is  an  endotoxin,  and 
it  is  probable  that  spontaneous  recovery  is  due  to 
the  development  of  sufficient  specific  antibodies  to 
enable  the  phagocytic  cells  to  digest  the  microbes 
they  so  readily  ingest,  for,  during  the  acute  stages, 
the  ingested  microbes  do  not  appear  to  be  in  the 
least  affected  by  the  ferments  of  the  leucocyte. 
Inoculation  with  efficient  antigen  brings  this  condi- 
tion about,  as  a  rule,  with  certainty  and  rapidity. 

Prophylaxis. — The  best  prophylactic  measure  is 
the  abstention  from  illicit  sexual  intercourse,  a 
counsel  of  perfection  which  will  never  be  attained 
as  long  as  the  sexual  instinct  is  one  of  the  most 
powerful  forces  in  nature.  Failing  abstention, 
washing  the  penis  with  an  efficient  antiseptic,  such 
as  3  per  cent,  carbolic  solution,  will  probably 
prevent  infection  in  the  majority  of  cases,  if  applied 
at  once  after  copulation. 

Treatment, — I  am  afraid  '  an  attack  of  the  clap  ' 
is  frequently  not  at  all  regarded  seriously  enough. 
The  consequences  of  neglect  of  efficient  treatment 
are  so  serious  that  it  is  quite  worth  while  to  take 
the  trouble  of  making  an  autogenous  vaccine. 

Acute  Stages. — Pending  the  production  of  an 
autogenous  vaccine  the  patient  should  be  given  a 
dose  of  stock  vaccine  which  should  be  made,  if 

137 


Therapeutic  Immunisation. 


possible,  from  the  strain  prevalent  in  the  neighbour- 
hood from  which  the  patient  got  the  infection  or, 
at  any  rate,  be  made  from  many  strains.  Much  of 
the  vaccine  to  be  obtained  commercially  is  quite 
useless.  The  microbe  from  which  the  stock  vaccine 
is  made  must  be  grown  on  fresh  human  blood.  If 
the  antigen  is  efficient  a  dose  of  2j  million  is  quite 
large  enough  to  start  with,  and  the  progression 
5,  10,  20,  is  suitable.  The  first  dose  of  the  auto- 
genous vaccine  is  the  next  dose  of  the  series  begun 
with  the  stock  vaccine.  The  series  continues  40,  80, 
120,  200,  and  so  on,  if  necessary.  The  intervals 
depend  on  reactions.  The  urethra  of  the  patient 
should  be  kept  flushed  out  by  making  him  drink 
plenty  of  water,  and  his  urine  should  be  kept 
amphoteric  by  giving  him  citrate  of  soda,  i  gramme 
(15  grains)  four  times  a  day  is  usually  sufficient. 
If  on  culture  another  or  other  microbes  grow,  they 
must  be  included  in  the  vaccine.  I  do  not  believe 
in  douching.  I  think  it  is  in  most  hands  liable  to 
spread  the  infection  backwards. 

I  know  a  large  number  of  cases  of  acute  gonor- 
rhoea get  well  of  themselves  or  by  ordinary  methods, 
but  I  see  too  many  chronic  cases  to  think  these 
methods  very  efficient. 

Chronic  Cases, — Still  more  inefficient  is  the  ordi- 
nary treatment  of  gleet  or  prostatis.  Posterior 
urethral  douches  to  kill  microbes  deep  in  the  tissue 
of  the  prostate  are,  to  my  mind,  ridiculous. 

Perhaps  the  most  common  combination  of 
microbes  in  these  conditions  is  staphylococci  and 
diphtheroids ;  the  other  microbes  already  mentioned 

138 


Urino-Genital  System. 


are  also  quite  common.  The  gonococci  have  fre- 
quently disappeared,  but  an  efficient  gonococcus 
vaccine  must  always  be  included  in  the  mixed 
vaccine  used,  as  this  microbe  may  be  still  lurking 
deep  in  the  tissues  and  not  appear  in  the  discharge. 
The  initial  dose  of  the  staphylococcus  vaccine  is 
25  million,  of  all  the  others  million.  So  that  if 
staphylococci  and  diphtheroids  grow  the  doses 
would  be  25  million  staphylococci,  2-|  million 
diphtheroids,  and  2J  million  gonococci,  and  the 
ascending  series  : — 

50+5+5 
100  +  10  +  10 
200  +  15  +  15 
400  +  20  +  20 
600  +  40  +  40 
800  +  80  +  80 
1,000   +  120   +  120 

2,000  +  200  +  200,  and  so  on,  if  necessary. 
The  intervals  depend  entirely  on  the  presence  or 
absence  of  reactions.  As  a  rule,  one  or  two  clear 
days  between  the  earlier  doses,  increasing  to  a  week 
between  the  larger  are  suitable  intervals.  As  before, 
the  urine  must  bekeptamphotericwithsodium citrate. 

It  is  essential  periodically  and  methodically  to 
massage  the  prostate,  if  enlarged,  through  the 
rectum. 

Female  Genital  Organs. 

Gonorrhea. — The  gonococcus  infects  the  vulva, 
first  producing  swelling,  oedema  and  ulceration  of  the 
labia,  urethritis,  inflammation  of  the  vaginal  glands, 

139 


Therapeutic  Immunisation. 


including  the  ducts  and  glands  of  Bartholini ;  the 
vaginal  wall  is,  as  a  rule,  not  so  much  affected.  The 
infection,  if  not  checked,  spreads  up  the  cervix  and 
uterus  to  the  tubes,  producing  pyosalpinx  and 
sterility.  Adhesions  of  the  fimbriated  end  to  the 
ovary  may  occur  with  abscess  formation  in  the 
latter. 

As  in  the  male,  when  the  inflammation  becomes 
chronic  the  gonococci  may  disappear  and  other 
microbes  continue  the  condition.  These  are  much 
the  same  as  those  in  the  male.  That  the  gono- 
coccus  may  lurk  deep  in  the  tissues  is  shown  by  the 
fact  that  sometimes  the  gonococcus  may  be  isolated 
during  or  just  after  menstruation,  but  not  during 
the  intervals.  The  principles  of  treatment  are 
identical  with  those  described  for  the  male. 

It  is  a  question  worth  considering,  whether 
prophylactic  inoculation  of  prostitutes  might  not 
reduce  the  case  incidence.  Other  cases  of  vaginitis 
occur  caused  by  other  micro-organisms,  the  flora 
being  very  various.  The  infection  is  usually  a 
mixed  one,  and  some  of  the  causative  microbes  I 
have  found  were  not  referrable  to  any  described 
group. 

Acute  Endometritis  occurs  during  the  puer- 
perium,  the  infection  being  introduced  by  hands  or 
instruments  or  is  due  to  spread  of  infection  from  a 
preceding  vaginitis. 

Pathology. — Septic  infection  occurs  chiefly  at  the 
placental  site  where  there  are  areas  of  necrosis  ; 
the  rest  of  the  endometrium  is  acutely  inflamed. 
Septic  thrombosis  occurs  in  the  veins,  and  the 

140 


Urino-Genital  System. 


lymphatics  become  infected  and  form  large  swellings 
with  smooth  inner  walls  filled  with  pus  (Shennan). 
Puerperal  fever  is  always  a  septicaemia  or  pyaemia. 
I  have  no  belief  in  sapraemia  as  a  probable  clinical 
entity.  Pyaemia  is  due  to  detachment  of  pieces  of 
septic  clot  in  the  veins.  The  infection  frequently 
spreads  to  the  pelvic  cellular  tissues,  and  not 
infrequently  to  the  peritoneum. 

Bacteriology, — Streptococci,  staphylococci,  and 
Bacillus  coli  are  much  the  most  common  causes. 
Quite  commonly  the  infection  is  mixed,  staphy- 
lococci and  streptoccoci,  or  either  of  them  with  the 
5.  coli.  Much  less  commonly  other  microbes,  such 
as  Micrococcus  catarrhalis  are  the  cause. 

Blood  cultures  and  cultures  from  the  interior  of 
the  uterus  must  be  made  at  once  before  any  douch- 
ing, except  a  vaginal  douche  with  sterilised  water  or 
normal  saline.  An  antiseptic  intrauterine  douche 
before  making  a  culture  may  take  away  a  patient's 
one  chance  of  survival. 

Cultures  should  be  made  on  a  blood  agar,  a 
McConkey  plate  (or  a  plate  of  other  differential 
medium)  and  in  broth.  The  blood  culture  in  broth 
should  be  kept  shaken  occasionally  during  the  first 
quarter  of  an  hour  or  contain  a  little  liquor  pan- 
creaticus  to  prevent  the  blood  clotting  (Douglas). 
Subcultures  may  be  made  in  twelve  hours.  Smears 
stained  by  Gram's  method  may  give  one  an  idea 
what  the  causative  infection  is,  but  it  is  frequently 
impossible  in  smears  to  differentiate  between 
staphylococci  and  short-chained  streptococci.  One 
blood-agar  plate  should  be  plentifully  inseminated 

141 


Therapeutic  Immunisation. 


with  the  pus  so  that  sufficient  growth  may  be 
present  in  twelve  hours  to  make  a  vaccine  if  it  is  a 
pure  culture. 

Prophylaxis  is,  as  a  rule,  outside  the  sphere  of 
vaccine  therapy.  If,  however,  the  patient  has  a 
history  of  infection,  after  one  or  more  previous  con- 
finements, or  has  an  obvious  mucopurulent  discharge, 
a  bacteriological  investigation  of  the  cervix  should 
be  made  and  a  course  of  vaccine  given. 

Treatment. — At  once,  besides  the  usual  focal  treat- 
ment, a  dose  of  stock  vaccine,  containing  the  three 
commonest  causes,  should  be  given,  viz.,  25  million 
staphylococci,  2-|  million  each  of  streptococci  and 
Bacillus  coli.  If  the  smear  shows  cocci  the  vaccine 
may  be  usefully  accompanied  by  25  c.c.  antistrepto- 
coccus  serum.  As  soon  as  possible  an  autogenous 
vaccine  should  be  prepared.  This  can  often  be  ready 
within  eighteen  hours.  The  initial  doses  are  25 
million  for  staphylococci,  2|  million  for  B.  coli  and 
streptococci  and  for  most  of  the  other  microbes 
which  may  be  exceptionally  isolated.  The  series  is 
for  staphylococci  25,  50,  75,  100,  150,  200  million, 
for  the  others  2|,  5,  7I,  10,  15,  20.  It  is  always  well 
to  give  several  increasing  doses  after  the  temperature 
has  permanently  subsided  to  guard  against  chronic 
endometritis.  The  intervals  are  judged  according 
to  the  rules  laid  down  for  acute  infection  (see  p.  62). 

Acidosis  must  be  guarded  against  by  giving 
sodium  citrate,  15 — 20  grains  every  four  hours. 

In  very  severe  infections  intravenous  anti- 
septics may  be  very  helpful.  Iodine  preparations 
may  be  used  first,  iodoform  in  ether,  66  mg.  (i  grain) 

142 


Urino-Genital  System. 


in  I  c.c.  pure  ether  given  intravenously  daily,  or 
di-iodosalicjdic  acid,  3 — 5  c.c.  of  a  i  per  cent, 
solution  of  the  sodium  salt  given  intravenously 
daily.  If  these  do  not  appear  to  be  working, 
chlorine  preparations  may  be  tried,  such  as  chlora- 
mine  T  or  Eusol.  I  have  had  some  very  promising 
results  with  di-iodosalicylic  acid  in  septicaemias, 
except  in  the  typhoid  and  paratyphoids. 

Extract  of  the  posterior  lobe  of  the  pituitary 
gland  should  be  given  so  as  to  keep  the  uterus 
contracted  and  so  help  to  expel  septic  material 
and  lessen  the  area  and  channels  of  septic  absorption. 

Chronic  Infections. — Chronic  endometritis  with  a 
white  discharge  is  one  of  the  most  common  causes 
of  ill-health  in  women  and,  in  many  cases,  one  of  the 
most  obstinate  to  cure  by  ordinary  methods.  There 
can  be  little  doubt  that  the  chronic  irritation  pro- 
duced by  microbes  is  the  most  common  cause  of 
cancer  of  the  uterus  in  women,  when  the  environ- 
ment for  its  development  is  suitable. 

Pathology, — The  mucous  membrane  becomes 
thickened,  oedematous  and  vascular,  and  there  is  a 
great  increase  in  the  size  or  number  of  the  glands, 
which  may  grow  on  to  the  vaginal  aspect  of  the 
cervix,  producing  '  erosions.'  Later  the  glands  may 
atrophy.  Continued  hypertrophy  of  the  mucous 
membrane  in  a  particular  situation  leads  to  the 
formation  of  a  polypus.  In  some  cases  there  is 
infiltration  with  leucocytes.  Although  the  bacteri- 
ology of  these  cases  has  not  been  worked  out  on  a 
large  scale,  yet  in  the  cases  I  have  investigated  I 
have  always  found  a  microbial  cause.    The  most 

143 


Therapeutic  Immunisation. 


common  infections  are  staphylococci  or  Bacillus  coli. 
In  a  case  of  membranous  endometritis  I  isolated 
Micrococcus  tetragenus  in  pure  culture;  in  another 
case  the  condition  was  due  to  a  mixed  infection  with 
Bacillus  coli  and  diphtheroid  bacilli.  This  patient 
suffered  from  a  most  irritating  herpetic  irruption 
of  the  vulva,  the  irruption  spreading  even  up  to 
the  mons.  From  the  blebs  the  diphtheroid  bacilli 
were  isolated  in  pure  culture. 

One  case  with  an  irritating  vaginal  discharge 
had  been  operated  on  three  times  for  recurrent 
epithelioma  of  the  vulva.  Coliform  bacilli  were 
isolated  from  the  discharge  ;  the  discharge  cleared  up 
with  a  full  course  of  vaccine.  There  has  been  no  re- 
currence, so  far,  of  the  epithelioma  (over  three  years). 

To  obtain  cultures,  after  thorough  douching  of  the 
vagina  with  sterile  water  a  speculum  is  passed,  the 
uterus  pulled  down  with  a  bullet  forceps  and  the 
platinum  loop  passed  up  into  the  interior  of  the 
uterus.  Cultures  are  made  on  agar  or  blood-agar 
slopes  or  plates. 

Treatment. — As  in  other  chronic  conditions  a 
large  dose  will  generally  have  to  be  attained  before 
a  permanent  effect  is  obtained.  The  initial  dose  of 
staphylococcus  vaccine  is  lOO  million  and  of  the 
others  2-|  million.  It  is  usually  necessary  to  attain 
a  dose  of  4,000  million  in  the  case  of  staphylococcus 
infection  and  a  dose  of  500 — 1,000  miUion  in  other 
infections.  As  in  all  cases  in  women  it  is  inadvisable 
to  give  a  dose  for  the  two  days  before  and  the  first 
two  days  of  menstruation. 

Adjuvant  Treatment. — Testicular  substance,  10 
144 


Urino-Genital  System. 


grains  three  times  a  day,  will  be  found  to  tone  up 
the  uterus  and  reduce  menorrhagia.  In  some  cases 
a  curetting  of  the  hypertrophied  mucous  membrane 
will  hurry  matters  up. 

Fallopian  Tubes  and  Ovaries. — These  are  so 
inaccessible  that  they  cannot  be  examined  direct. 
Generally,  the  cause  of  salpingitis  is  the  same  as  that 
of  endometritis.  In  acute  pus  tubes  and  abscess  of 
the  ovary  the  immunisator  may  be  able  to  help  the 
surgeon  to  do  conservative  surgery  with  increased 
prospect  of  success.  The  successful  reproductive 
results  in  some  cases  produced  by  a  small  piecj  of 
ovary  attached  near  the  opening  of  the  stump  ol 
an  amputated  Fallopian  tube  are  most  remarkable. 

Successful  early  inoculation  of  gonorrhoeal  infec- 
tion in  the  female  ought  to  prevent  such  cases 
occurring. 


145 


10 


CHAPTER  IX. 


BONES,  JOINTS,  WOUNDS. 

Acute  Osteomyelitis. — The  initial  symptoms 
are  constantly  mistaken  for  those  of  acute  rheu- 
matism, from  which  conditions  the  diagnosis  at  first 
may  be  very  difficult  if  the  site  of  the  infection  is 
near  a  joint. 

Pathology. — The  inflammation  may  start  either  in 
the  periosteum,  medulla,  or  both,  and  may  occur  in 
the  diaphysis  or  epiphysis;  a  sKght  injury  usually 
determines  the  site.  Pus  forms  in  the  marrow  and 
under  the  periosteum,  and  this  is  followed  by  osteitis 
and  necrosis  of  the  bone  itself.  The  inflammation 
spreads  to  overlying  tissues  and  may  work  through 
the  cartilage  into  joints.  If  the  patient  does  not  die 
of  pj^aemia  the  disease  becomes  chronic  and  new  bone 
is  laid  down  by  the  periosteum,  the  dead  bone  inside 
forming  a  sequestrum  lying  in  an  abscess  cavity.  In 
cancellous  bone  if  the  suppuration  becomes  chronic, 
an  abscess  is  present  surrounded  by  dense  bone. 

Bacteriology, — The  causative  microbe  is  isolated 
from  the  pus  after  incision  of  the  periosteum  and, 
if  necessary,  trephining. 

The  most  common  microbes  are  Staphylococcus 
aureus,  albus  or  citreus,  or  streptococci. 

Prophylaxis, — The  patient  must  have  been  suffer- 
ing from  a  chronic  septicaemia  with  the  microbe  found. 
It  becomes  more  virulent  on  growth  in  the  tissues 

146 


Bones,  Joints,  Wounds. 


whose  resistance  have  been  lowered  by  injury  or 
other  causes.  The  source  of  these  microbes  is  some 
badly  locahsed  infection,  such  as  pyorrhoea  alveo- 
laris,  tonsiUitis  or  gastroenteritis.  As  in  other  cases, 
prophylaxis  consists  in  clearing  up  such  infections 
with  appropriate  vaccines  and  local  treatment. 

Treatment, — The  surgical  treatment  must  be 
prompt  and  energetic,  free  incision  and  trephining 
of  the  patient's  limb,  if  life  is  to  be  saved.  As  soon 
as  possible  a  vaccine  should  be  prepared.  It  is 
usually  possible  to  have  it  ready  in  fourteen  to 
eighteen  hours.  Cultures  should  be  made  on  agar 
or  blood-agar  and  in  broth — in  the  latter  to  dis- 
tinguish, as  soon  as  possible,  between  staphylococci 
and  streptococci.  The  initial  dose  of  staphylococcus 
vaccine  is  25  million,  and  the  progression  25,  50, 
75,  100,  150,  200,  and  so  on.  In  chronic  cases,  in 
which  there  is  often  chronic  pyaemia  or  septicaemia 
with  multiple  abscesses,  very  high  doses  may  have 
to  be  attained.  In  one  case  due  to  Staphylococcus 
albus  I  attained  a  dose  of  30,000  million  before  the 
patient  remained  permanently  well. 

The  initial  dose  of  streptococcus  vaccine  is 
2j  million,  and  the  progression  2J,  5,  7I,  10,  15,  20, 
30,  50,  75,  100  million,  and  so  on.  The  intervals 
depend  on  presence  or  absence  of  reactions.  Of 
course,  sequestra  must  be  removed  as  soon  as  they 
become  loose. 

Acute  Suppurative  Arthritis  occurs  in 
pyaemia  and  septicaemia  or  is  the  result  of  spread 
of  infection  from  neighbouring  bones. 

Pathology. — The  synovial  membrane  becomes  infil- 
147 


Therapeutic  Immunisation. 


trated  with  inflammatory  exudate  and  cells,  the 
lining  cells  desquamate,  and  there  is  increased 
secretion  of  synovial  fluid  which  becomes  purulent. 
If  suitable  treatment  is  not  used,  or  is  unsuccessful, 
and  the  patient  lives,  the  membrane  becomes  con- 
verted into  a  layer  of  granulation  tissue.  The 
articular  cartilages  become  vascularised,  infiltrated 
and,  finally,  eroded,  so  that  the  end  of  the  bone  is 
left  bare.  The  underlying  bone  undergoes  a  rare- 
fying osteitis  and  necrosis.  The  capsule  and  liga- 
ments are  infiltrated  and  softened,  so  that  spon- 
taneous dislocation  may  occur. 

Bacteriology  and  Treatment, — At  once  in  acute 
synovitis  not  due  to  injury  the  joint  should  be 
aspirated  and  cultures  made.  In  bone  disease  the 
cause  is  usually  staphylococci  or  streptococci  and 
the  treatment  that  already  described.  In  typhoid 
and  paratyphoids  it  may  be  due  to  the  causative 
bacilli.  In  scarlet  fever  it  is  usually  due  to  strepto- 
cocci. In  other  cases  it  may  be  due  to  other  microbes, 
such  as  the  Bacillus  coli  or  pneumococcus.  The 
initial  dose  of  all  these  microbes  is  2\  million,  and 
the  progression  2|,  5,  7^,  10,  15,  20,  30,  50,  75, 
100  million,  and  so  on. 

If  the  joint  is  to  be  saved  treatment  must  be 
prompt  and  energetic.  Repeated  aspiration  or  free 
drainage  is  essential. 

In  both  acute  suppuration  of  bones  and  joints 
intravenous  antiseptics  are  often  a  most  useful 
adjuvant  treatment  ;  3 — 5  c.c.  of  a  o'l  per  cent, 
solution  of  sodium  salt  of  di-iodosalicyclic  acid,  or  if 
this  fails,  eusol  or  chloramine  T.  should  be  tried. 

148 


Bones,  Joints,  Wounds. 


Rheumatism. — Rheumatic  conditions,  like  many 
others,  appear  to  be  septicaemias,  with  focal  mani- 
festations. In  typhoid  fever,  for  instance,  the  focal 
manifestations  are  in  the  intestine  ;  in  pneumonia, 
in  the  lungs  ;  in  rheumatic  infections,  in  the  joints, 
muscles,  or  nerves,  while  other  organs,  such  as  the 
heart  and  kidneys,  may  be  involved. 

The  clinical  conditions  fall  naturally  into  two 
groups — the  acute  and  chronic ;  and  this  classifica- 
tion is  suitable  pathologically,  for  the  chronic  cases, 
unless  sometimes  when  they  are  a  sequel  to  the 
acute,  are  usually  complicated  by  secondary  infec- 
tions, while  the  acute  conditions  are  generally 
produced  by  a  single  infection.  They  all  appear  to 
agree  in  having  a  primary  focus  of  infection,  from 
which  the  blood  and  other  tissues  become  infected. 
Acute  non-suppurative  inflammations  of  joints 
occur  in  rheumatic  fever,  gonorrhoeal  infections, 
and  acute  gout.  Acute  gout  will  be  considered 
with  the  chronic  variety ;  acute  gonorrhoeal  arthritis 
need  not  be  considered  here. 

Pathology, — In  Rheumatic  Fever  the  most 
common  primary  focus  of  infections  is  in  the 
tonsils,  adenoids  or  gums  ;  from  these  the  blood 
stream  becomes  infected  via  the  lymphatics.  The 
onset  of  the  fever  is  accompanied  by  lesions  in  the 
joints,  where  there  is  considerable  inflammatory 
infiltration  of  the  subsynovial  and  periarticular 
tissues,  the  cartilages  are  swollen,  their  cells  pro- 
liferated, and  there  is  more  or  less  effusion  into 
the  joints.  Lesions  in  other  tissues  may  follow — 
endocarditis    (which   is    the    rule    rather  than 

149 


Therapeutic  Immunisation. 


the  exception),  myocarditis,  pericarditis,  pleurisy, 
pneumonia. 

Bacteriology, — The  causal  organism  has  been 
studied  by  many  people,  notably  Poynton  and  Payne 
and  Beattie,  and  has  received  various  names — e.g.,  the 
Diplococcus  rheumaticus.  It  is  morphologically  and 
culturally  identical  with  the  streptococcus  commonly 
found  in  pyorrhoea  alveolaris,  tonsils  and  adenoids. 
It  can  be  isolated  from  the  primary  lesion,  from  the 
joints,  from  the  blood,  and  it  will  most  probably  be 
found  in  the  urine  and  faeces  in  these  cases.  As  in 
the  case  of  all  other  microbes,  its  virulence  varies. 

Prophylaxis. — Since  there  is  nearly  always  a 
primary  lesion  in  the  regions  already  indicated,  and 
this  lesion  is  usually  present  for  a  longer  or  shorter 
time  before  the  symptoms  of  acute  general  infection 
arise,  it  is  obvious  that  the  clearing  up  of  such 
training  grounds  for  pathogenic  microbes  will  prevent 
the  onset  of  the  general  infection.  Tonsils  and  ade- 
noids should  be  removed,  the  streptococcus  isolated 
from  them  or  from  the  pus  from  the  gum,  if  that  is 
the  lesion,  and  a  course  of  vaccine  given.  The 
sequence  of  doses,  2i,  5,  7I,  10,  15,  20,  30,  50,  75, 
100  million,  will  usually  be  found  suitable  and 
adequate.  Care  must  be  taken  that  the  patient 
should  not  be  over-fatigued  or  exposed  to  chill  for 
twenty-four  hours  after  a  dose.  The  intervals  must 
be  regulated  by  the  occurrence  of  reactions.  No 
dose  must  be  given  with  a  shorter  interval  than 
forty-eight  hours.  If  reactions,  focal  or  general, 
occur,  the  next  dose  must  not  be  given  until  three 
days  after  all  signs  of  reaction  have  disappeared. 

150 


Bones,  Joints,  Wounds. 


Treatment. — I  think  I  may  fairly  state  that  the 
sole  methods  of  treatment  at  present  in  use  are  rest 
and  salicylates.  As  to  the  adequacy  of  these 
measures,  I  will  quote  an  article  by  French  in  the 
Medical  Annual  for  1916.  He  says  :  The  fact 
that  salicylates  in  rheumatic  fever  do  practically 
nothing  towards  curing  the  disease  is  apt  to  be  lost 
sight  of.  What  salicylates  do  is  to  bring  down  the 
temperature  and  reheve  the  joint  pains,  an  immense 
boon  to  the  patient,  but  the  pains  will  recur  if  the 
salicylates  are  stopped,  up  to  a  period  which  is 
approximately  the  same  as  used  to  be  the  case  before 
salicylates  were  employed.  ...  It  is,  however, 
probable  that  the  mere  fact  that  salicylates  relieve 
the  joint  pains  renders  the  severity  of  the  subsequent 
valvular  heart  disease  even  greater  than  before  ; 
for  endocarditis  is  not  prevented  by  salicylates,  and 
some  patients  who  would  rest  in  bed  longer,  if  they 
were  in  pain,  get  up,  and  add  unnecessary  strain  to 
their  inflamed  heart  valves  ;  when  not  being  in 
pain,  they  believe  they  are  cured  of  their  acute 
rheumatism." 

The  universal  method  of  treatment  then  is  entirely 
inadequate,  either  to  cure  the  disease  or  prevent 
relapse. 

My  personal  opinion  is  that  a  combination  of 
chemo-  and  immuno-therapy  will  give  the  best 
results.  I  know  from  clinical  experience  that  an 
iodine  salicylic  acid  compound  in  the  form  of  the 
sodium  salt  of  the  di-iodosalicylic  acid  is  a  powerful 
intravital  killer  of  streptococci,  and  I  think  it  would 
be  well  worth  a  trial  in  acute  rheumatism.  The  doses 

151 


Therapeutic  Immunisation. 


I  would  suggest  would  be  2  to  5  c.c.  of  a  i  per  cent, 
solution  given  daily  intravenously. 

As  soon  as  possible  an  autogenous  vaccine  should 
be  made,  the  dose  being  2|,  5,  7I,  10,  15,  20  million, 
and  more  if  necessary.  Even  if  a  vaccine  is  not  used 
in  the  acute  stage,  as  I  am  quite  sure  it  should  be, 
it  should  be  used  in  order  to  prevent  relapse,  which  is 
notoriously  common  after  an  attack. 

Acidosis — so  constant  in  the  disease — should  be 
combated  by  giving  sodium  citrate  until  the  urine  is 
amphoteric. 

Chronic  Rheumatism. 

Pathology, — In  subacute  and  chronic  rheumatism 
the  exudate  in  the  joint  and  surrounding  tissues 
becomes  gradually  organised.  The  cartilages  may 
be  at  first  unaffected,  or  may  be  so  only  near  their 
margins,  where  they  may  become  eroded.  Later 
these  erosions  may  spread  until  the  whole  cartilage 
is  destroyed,  and  bony  ankylosis  may  result  from 
spread  of  the  infection  to  the  bones  {rheumatoid 
arthritis).  In  other  cases  the  cartilages  may  be 
eroded  and  destroyed  where  there  is  pressure,  while 
they  become  hypertrophied  and  ossified  at  the  edges, 
so  as  to  produce  osteophytes,  some  of  which  may 
be  broken  off,  and  become  loose  in  the  joints. 
Where  the  bare  bones  are  in  contact,  they  become 
polished  and  atrophied.  This  atrophy  may  be  so 
extreme  that  eventually  the  whole  head  of  the  bone 
disappears  {arthritis  deformans) . 

In  chronic  gout  sodium  urate,  or  the  urates  of 
calcium,  magnesium,  or  ammonium,  become  de- 


Bones,  Joints,  Wounds. 


posited  in  the  articular  cartilage,  which  becomes 
eroded.  Later  these  urates  become  deposited  in 
the  synovial  membrane,  periarticular  tissues,  liga- 
ments, tendon  sheaths  in  the  periosteum,  bursae, 
deep  connective  tissues,  and  subcutaneous  tissue. 

Chronic  rheumatism  attacks  men  and  women  of 
all  ages,  and  gout  attacks  people  from  middle  age 
onwards,  who  are  usually  of  an  alcoholic  habit. 
Rheumatoid  arthritis  affects  people,  usually  females, 
between  20  and  40,  and  arthritis  deformans  is  com- 
monest in  females  between  40  and  60. 

I  am  perfectly  aware  that  it  is  the  general  opinion 
that  each  of  these  clinical  conditions — rheumatism, 
rheumatoid  arthritis,  arthritis  deformans  and  gout 
— has  a  different  etiology.  I  have  reason  to  think, 
however,  that  this  is  not  the  case,  but  that  the 
mechanism  of  their  production  is  the  same,  and 
that  the  differences  in  the  pathological  condition 
are  due  to  differences  in  the  quality  of  either  the 
toxins  or  the  tissues  attacked  by  them,  and  the 
quantity  of  urates  in  the  patient's  circulation.  This 
opinion  has  been  reached  as  the  result  of  observing 
that  they  all  have  similar  foci  of  infection  other  than 
those  of  the  joints,  and  as  the  result  of  favourable 
effects  on  the  joint  conditions  produced  by  measures 
adopted  to  cure  these  other  lesions.  For  the  large 
majority  of  all  such  patients  have  chronic  infections 
in  the  upper  alimentary  or  respiratory  tract,  the 
microbes  from  which  can  and  do  infect  the  rest  of 
the  gastrointestinal  tract,  which  is  evident  from 
signs  and  symptoms.  These  microbes  produce  the 
primary  infection,  and  lower  the  resistance  of  the 

153 


Therapeutic  Immunisation. 


tract ;  the  colif orm  microbes  inhabiting  the  intestine 
then  become  pathogenic,  so  that  there  is  a  mixed 
infection.  This  chronic  inflammation  not  only 
interferes  with  normal  digestion  by  interfering  with 
the  proper  production  of  digestive  enzymes,  but 
also  produces  abnormal  breakdown  products  of 
ingested  foodstuffs,  such  as  abnormal  amino-acids, 
abnormal  in  quality  and  quantity,  besides  aromatic 
amine  compounds,  which  produce  rise  of  blood 
pressure.  In  addition  to  the  chronic  infection  in 
the  intestinal  tract,  there  can  be  no  doubt  that 
microbes  from  the  foci  of  infection,  both  primary  and 
intestinal,  are  passing  continually  into  the  circula- 
tion. Quite  commonly  such  microbes  are  excreted 
by  the  kidneys,  and  can  be  isolated  from  the  urine. 

There  are  thus  continuously  passing  into  the 
blood  products  from  normal  and  abnormal  digestion 
and  micro-organisms.  As  a  rule,  much  more  protein 
than  is  necessary  for  nitrogenous  equilibrium — that 
is,  for  the  maintenance  of  the  nitrogen  element  in 
the  structure  of  the  protoplasmic  molecule — is 
ingested.  The  superfluous  amino-acids  to  which  it 
is  reduced  are  deaminised,  in  the  intestinal  cells 
especially,  and  in  the  muscles,  and  the  resulting 
ammonia  is  synthesised  into  urea  in  the  liver. 

In  fatigue  of  the  muscles  and  in  abnormal  meta- 
bolism produced  by  fever,  where  there  is  anoxaemia, 
acids  are  formed,  such  as  sarcolactic  acid,  and  these, 
getting  into  the  circulation,  interfere  with  the 
normal  metabolism,  since  the  intracellular  and  tissue 
ferments  work  best  in  an  alkaline  medium.  Any- 
thing that  leads  to  an  increase  of  acids  from  the 

154 


Bones,  Joints,  Wounds. 


intestine,  such  as  are  produced  from  deaminised 
amino-acids,  will  aggravate  the  condition,  or  any 
poison  which  interferes  with  oxidation  in  the  tissues, 
such  as  alcohol.  Again,  the  interference  with  the 
oxidation  in  the  tissue  cells  may  be  due  to  microbial 
infection.  I  have  had  one  patient  in  whom  an  acute 
exacerbation  of  gout  was  brought  on  by  over-indul- 
gence in  tobacco. 

In  all  these  conditions  an  abnormal  amount  of 
uric  acid  appears  to  be  formed — and  it  is  not — as  it 
is  normally — changed  into  the  harmless  urea.  In 
gout  it  is  deposited  in  the  inflamed  tissues  in  the 
form  of  salts. 

To  sum  up,  the  original  condition  appears  to  me 
to  be  produced  by  microbes  from  a  focus  of  infection, 
supplemented  by  secondary  infections,  and  is 
maintained  by  vicious  circles  produced  by  the 
abnormal  metabolic  products  formed — {a)  in  the 
intestine,  (&)  in  the  tissues. 

Such  is  the  hypothesis  on  which  the  treatment  of 
these  conditions  is  founded.  If  it  is  correct,  then 
removal  of  the  infecting  focus  and  reduction  of  the 
action  of  the  microbes  in  the  intestine  ought  to  pro- 
duce cure  if  the  tissues  affected  are  not  too  damaged 
to  allow  of  this  result.  And  this  I  have  found  to  be 
so.  By  the  methods  described  below  several  cases  of 
typical  gout  have  been  cured. 

Prophylaxis. — As  in  the  acute  cases,  the  prophy- 
laxis of  chronic  rheumatic  joints  consists  in  the 
clearing  up  of  the  sources  of  infection  that  pro- 
duced them.  The  first  twinge  of  rheumatic  pain 
should  be  sufficient  warning  to  the  patient  that  he 


155 


Therapeutic  Immunisation. 


must  have  his  microbial  inhabitants  investigated, 
his  foci  of  infection  cleared  up,  and  his  resistance  in- 
creased to  the  microbial  inhabitants  of  his  intestine. 

Treatment  consists  in  inoculation  with  a  vaccine 
made  from  the  microbes  found  in  the  focus  of 
infection,  with  a  vaccine  made  from  the  patient's 
coliform  bacilli  and  with  a  vaccine  made  from  any 
microbe,  other  than  B,  coli  or  streptococci,  which  is 
being  excreted  from  the  patient's  urine.  If  staphy- 
lococci are  being  excreted  by  the  kidneys,  strepto- 
cocci isolated  from  the  gums,  and  coliform  bacilli 
from  the  intestine,  the  series  of  doses  would  be  in  the 
order  mentioned  : — 


25 

million  + 

2j  million  + 

2j  million 

50 

5 

5 

75 

„  + 

71  , 

,  + 

5 

100 

„  + 

ID 

ID  „ 

150 

„  + 

15  , 

,  + 

15  „ 

200 

„  + 

20 

,  + 

20 

and  so  on  up  to 

2,000  +  200  +  200  million  or  more. 

Not  uncommonly  other  microbes  than  the  strepto- 
cocci are  responsible  for  the  primary  infection.  In 
several  cases  I  have  found  Gram-negative  bacilli, 
not  described,  in  the  gums  or  being  excreted  in  the 
urine.   The  initial  dose  of  these  is  2|  millions. 

One  such  bacillus  was  motile,  it  did  not  liquefy 
gelatine.  It  produced  acid,  but  no  clot  in  milk.  It 
produced  acid  and  gas  in  glucose,  saccharose  and 
mannite.  It  produced  acid  very  slowly,  but  no  gas 
in  lactose.  Another,  feebly  motile,  produced  acid 
in  saccharose  and  glucose.  It  did  not  ferment  lactose 

156 


Bones,  Joints,  Wounds. 


or  mannite  in  five  days,  and  produced  acid  and  clot 
in  milk.  Another,  non-motile,  produced  acid  in 
lactose,  saccharose  and  glucose,  but  not  in  mannite, 
and  acid  and  clot  in  milk.  So  that  many  different 
kinds  of  these  Gram-bacilli  appear  to  infect. 

The  correction  of  acidosis  is  particularly  important 
in  the  treatment  of  these  conditions,  and  the  control 
of  reactions  by  iodine  therapy  most  helpful. 

Muscles. — Muscular  rheumatism  or  fibrositis  is 
investigated  and  treated  in  exactly  the  same  manner 
as  that  of  the  joints. 

Infected  Wounds,  Compound  Fractures,  etc. 

Pathology. — The  cavity  of  the  wound  is  filled  with 
blood  clot,  and  this  clot  extends  along  the  blood 
vessels  as  far  as  the  nearest  uninjured  vessel  to 
which  it  is  joined.  Portions  of  tissue,  muscle,  bone, 
which  have  been  separated  off  from  their  nerve 
and  blood  supply  are  undergoing  necrosis.  In  the 
case  of  wounds  made  by  projectiles  there  is  the 
complication  of  the  presence  of  foreign  bodies,  metal, 
portions  of  clothing  and  suchlike. 

If  the  wound  is  aseptic  the  clotted  blood,  injured 
tissues,  and  so  on,  become  invaded  by  phagocytic 
cells  and  plasma  from  the  surrounding  uninjured 
capillaries.  Their  removal  is  also  brought  about  by 
autolysis  and  absorption  by  the  lymphatics  and  veins. 
In  the  case  of  necrosing  bone  the  process  is  so  slow 
that  it  acts  as  a  foreign  body.  When  the  effused 
blood  is  absorbed  the  fibrinous  exudate  is  organised 
by  the  invasion  of  fibroblasts,  derived  from  the 

157 


Therapeutic  Immunisation. 


division  of  connective  tissue  cells,  and  new  capil- 
laries are  formed  by  the  budding  of  cells  from  the 
walls  of  the  capillaries  which  join  together  and 
become  canalised.  These  are  later  obliterated  by  the 
fibrillation  and  contraction  of  the  matrix  in  which 
they  lie,  as  are  the  connective  tissue  cells  that  sur- 
round them.  The  surface  of  the  wound  is  covered  by 
the  spreading  over  it  of  epithelial  cells  derived  from 
the  deeper  layers  of  the  epidermis  round  its  margins. 
If  the  wound  is  infected  the  conditions  present  form 
a  perfect  culture  medium  for  the  development  of 
micro-organisms,  and  the  general  system  is  easily 
invaded  through  the  lymphatics  and  the  blood 
vessels,  the  clots  in  the  injured  branches  of  which 
become  infected. 

This  general  infection  is  aided  by  the  general 
lowering  of  the  activity  of  the  body  by  shock  and 
by  the  absorption  of  breakdown  products  produced 
by  normal  methods  and  the  action  of  bacterial 
ferments.  General  infection  is  '  especially  severe 
after  bone  injury,  owing  to  the  greater  difficulty  in 
it  of  walling  off  the  infection  by  the  processes  of 
inflammation.  It  is  evident  that  the  conditions 
must  be  suitable  for  the  bacillus  of  malignant 
oedema  and  of  the  B.  perfringens  to  produce  gas, 
since  these  microbes  are  often  isolatable  from 
wounds  where  no  gas  is  being  formed.  Probably  a 
sufficient  activity  of  aerobic  microbes  is  necessary 
to  produce  a  sufficient  degree  of  anaerobiosis.  The 
gangrene  is  largely  due  to  the  gas  separating  the 
tissue  elements  from  each  other  as  well  as  to  the 
toxins  of  the  microbes. 

158 


Bones,  Joints,  Wounds. 


Bacteriology. — The  most  common  aerobic  microbes 
found  in  infected  wounds  are  staphylococci,  jB.  pyo- 
cyaneus,  streptococci,  B.  coli,  other  coKform  baciUi, 
and  various  Gram-negative  baciUi  not  classified, 
some  of  which  are  gelatine  liquefiers,  and  probably 
belong  to  the  B,  proteus  group.  Diphtheroids  and 
other  Gram-positive  bacilli  are  also  very  common. 

Besides  these  aerobic  microbes  gunshot  and  other 
wounds  contaminated  with  soil  and  decomposing 
organic  matter  are  liable  to  become  infected  with 
anaerobic  microbes,  the  most  important  of  which  are 
the  tetanus  bacillus,  the  bacillus  of  malignant  oedema 
and  the  B,  perfrigens  {B.  aerogenes  capsulatus  of 
Welch).  All  these  microbes  are  spore-forming,  and 
the  last  two  produce  gas  in  the  tissues.  Gas  is 
also  produced  by  other  anaerobes  and  aerobes, 
e.g.,  B.  aerobicus  sepis,  but  they  are  rarer. 

Prophylaxis  and  Treatment. — Owing  to  the  great 
variety  of  microbes  found  in  infected  wounds  it  is 
practically  impossible  to  attempt  to  prevent  focal 
and  general  infection  by  the  use  of  stock  vaccines. 
The  prevention  of  severe  systemic  infection  and  of 
the  invasion  of  uninjured  tissues  is  in  the  hands  of 
the  surgeon,  whose  aim  must  be  the  most  complete 
possible  removal  of  foreign  bodies,  blood  clot  and 
free  drainage.  Wherever  possible  a  vaccine  con- 
taining all  the  aerobic  microbes  isolatable  from  the 
wound  grown  on  human  blood  agar  should  be  made 
at  the  earliest  moment  if  there  is  suppuration  with 
signs  of  general  infection.  This  is  additionally 
important  where,  as  is  usually  the  case  in  war, 
especially  on  cultivated  soil,  the  wound  is  infected 

159 


Therapeutic  Immunisation. 


with  soil  and  faecal  micro-organisms  containing 
anaerobic  gas- producing  microbes,  for  it  appears  that 
unless  aerobes  are  present  these  anaerobes  cannot 
produce  their  disastrous  results. 

My  own  opinion  about  the  saline-antiseptic  con- 
troversy is  that,  with  one  exception  perhaps,  no 
antiseptic  in  use  is  effective  in  the  depths  of  a  wound, 
for  seldom  does  it  get  there,  and  if  it  did,  it  would 
only  be  effective  in  such  a  strength  that  it  would  do 
more  harm  than  good  by  kiUing  the  tissue  cells  as 
well  as  the  microbes.  Sterile  isotonic  saline  is 
undoubtedly  the  best  fluid  to  use  for  the  early  wash- 
ing out  and  irrigation  of  a  wound.  When  specific 
antibodies  have  been  produced  by  the  proper  use 
of  vaccine  then  the  judicious  use  of  a  slightly 
hypertonic  saline  is  sometimes  useful,  but  it  must 
always  be  remembered  that,  as  Wright  has  demon- 
strated, it  has  an  antiphagocytic  action  and  should, 
if  used  at  all,  be  only  used  intermittently. 

The  antiseptic  I  hold  a  brief  for  is  iodoform.* 
When  split  up,  as  it  is  in  the  body,  especially  in  the 
presence  of  pus,  the  iodine  is  germicidal  ;  it  is 
antitoxic,  destroying  the  toxic,  but  not  the  antigenic 
property  of  microbial  toxins,  while  Hamburger  has 
demonstrated  the  fact  that  iodoform  as  such 
increases  the  phagocytic  power  of  phagocytic  cells. 
The  iodoform  must  be  dissolved  in  ether,  the  vapori- 
sation of  which  leaves  it  in  a  finely  divided  state  on 
the  surface  of  the  wound,  while  the  ether  itself 
has  an  antiseptic  action.     Sixty-six  milligrammes 

*  This  was  written  before  the  acryl  compounds  were  intro- 
duced.   I  have  no  practical  experience  of  these. 

i6o 


Bones,  Joints,  Wounds. 


(i  grain)  of  iodoform  are  soluble  in  i  c.c.  of  pure 
ether.  Ten  c.c.  containing  lo  grains  will  be  sufficient 
to  leave  a  fine  deposit  on  the  whole  surface  of  most 
wounds  if  injected  into  the  bottom  of  them,  and  in 
this  dose  is  not  likely  to  produce  iodoform  poisoning. 
Further,  the  absorption  of  iodoform  or  its  breakdown 
products  from  the  surface  of  the  wound  is  most 
valuable  in  combating  general  infection.  The  iodo- 
form in  ether  given  intravenously  in  doses  of  |  to 
I  grain  daily  is  extremely  valuable  for  this  purpose. 

Another  drug  which  is  most  valuable  for  combating 
general  infection  with  many  kinds  of  microbes  is 
di-iodosalicylic  acid  in  the  form  of  a  i  per  cent, 
watery  solution  of  its  sodium  salt ;  3 — 5  c.c.  is 
given  every  day  intravenously. 

Vaccines  are  especially  useful  when  there  is  acute 
general  infection,  where  the  wound  has  become  slug- 
gish and  indolent  and  where  the  patient  is  becoming 
cachectic.  Vaccines  will  hasten  the  heaUng  of  all 
suppurating  wounds. 

As  in  all  other  cases,  it  is  essential  for  success  that 
the  vaccine  should  contain  all  the  microbes  that  are 
infecting  the  patient,  that  the  doses  should  be 
steadily  increased  until  the  result  is  attained,  that 
the  vaccine  should  be  given  at  suitable  intervals, 
which  are  determined  by  the  absence  or  degree 
of  focal  and  general  reactions.  If  no  obvious 
reaction  occurs  the  next  dose  may  be  given  in  forty- 
eight  hours  ;  if  reactions  occur  the  next  dose  should 
not  be  given  for  three  days  after  all  signs  of  these 
reactions  have  disappeared.  If  the  reaction  is 
severe  after  an  injection  it  can  be  controlled  by 

161  " 


Therapeutic  Immunisation. 


intravenous  iodoform  or  di-iodosalicylic  acid  already 
mentioned,  or  iodine-menthol-radium  compound  in 
I  c.c.  doses  given  subcutaneously.  The  vaccine 
must  not  be  given  into  an  area  the  lymphatics  of 
which  drain  into  infected  lymphatic  glands. 

Frequently,  owing  to  the  profuse  growth  of  one 
microbe  in  the  primary  culture,  an  important 
microbe  may  be  missed ;  after  some  doses  this 
microbe  is  reduced  or  has  disappeared,  and  fresh 
culture  will  then  give  the  other  microbe.  A  mixed 
infection  containing  B,  pyocyaneus  is  a  good  example. 
This  poisonous  microbe  grows  very  freely  and  rapidly 
overgrows  everything  else.  The  original  smear  may 
show  other  microbes,  for  instance,  streptococci. 
A  B,  pyocyaneus  vaccine  is  made ;  a  dose  of  i  or  2 
million  is  quite  a  big  enough  initial  dose,  and  the 
series  2,  4,  8,  10,  15,  20,  given ;  a  fresh  culture  will 
then  enable  the  streptococcus  to  be  isolated.  If  the 
patient  is  not  doing  well  with  the  vaccine  his  flora 
should  be  reinvestigated,  for  the  wound  may  have 
become  invaded  with  other  microbes,  or,  as  we  have 
seen,  a  microbe  which  was  there  in  small  numbers,  as 
compared  with  the  others,  may  have  been  missed ;  as 
the  others  disappear  it  may  become  aggressive.  The 
initial  dose  of  staphylococci  is  25  million,  as  a  rule  ; 
if  the  case  is  very  acute  10  million  is  sufficient,  and 
the  series  50, 100,  150,  200, 400, 600,  800, 1,000, 1,500, 
2,000,  and  so  on  ;  2|,  5, 71, 10,  15,  20,  30,  50,  75,  100, 
150,  200,  or  higher,  in  the  case  of  all  the  others.  If 
the  general  infection  is  severe  the  progression  i,  2,  4, 
6,  8,  10,  15,  20,  and  so  on,  is  the  safest  to  use,  as  in 
the  case  of  the  Bacillus  pyocyaneus, 

162 


CHAPTER  X. 


THE  SKIN. 

Erysipelas  is  an  acute  spreading  inflamma- 
tion of  the  skin  accompanied  by  symptoms  of  acute 
generalised  infection.  It  is  caused  by  infection  with 
the  Streptococcus  erysipelatis.  There  is  a  definite 
spreading  edge,  the  inflammation  subsiding  behind 
it,  the  tissues  having  acquired  a  local  immunity. 

Pathology. — There  is  acute  hyperaemia  and  cellulo- 
fibrinous  exudation  into  the  dermis.  The  strepto- 
cocci are  found  in  the  tissues,  but  chiefly  in  the 
lymphatics,  along  which  they  spread.  The  cells 
of  the  epidermis  are  swollen  and  vacuolated,  and 
often  undergo  colliquative  necrosis,  forming  bullae. 
Frequently  the  infection  involves  the  subcutaneous 
tissues,  a  cellulitis  resulting.  Abscesses  may  form 
or  sloughing  of  the  skin  from  gangrene. 

Bacteriology,' — The  streptococci  which  have  no 
special  morphological  or  cultural  characteristics  are 
easily  isolated  from  the  blebs.  They  grow  strongly 
on  blood- agar. 

Treatment. — Specific  sera  are  obtainable  com- 
mercially, which  frequently  give  excellent  and  rapid 
results.  Twenty-five  c.c,  repeated  in  twenty-four 
hours,  is  a  suitable  dose  for  an  adult. 

Even  if  the  serum  is  successful  an  autogenous 
vaccine  is  necessary,  as  the  disease  is  very  liable  to 

163  ^^-^ 


Therapeutic  Immunisation. 


relapse.  The  dose  should  be  2|,  5,  7I,  10,  15,  20, 
increasing  to  50  or  100  miUion,  given  at  suitable 
intervals.  The  doses  should  be  given  subcutaneously 
into  an  area  as  far  away  as  possible  from  the  site  of 
the  disease.  Vaccine  and  serum  may  be  given 
together  as  soon  as  the  vaccine  is  available. 

Anthrax. — The  anthrax  bacillus  produces  two 
kinds  of  lesions  in  man,  viz.,  *  malignant  pustule  ' 
of  the  skin  and  acute  inflammation  of  the  lungs,  or 
'  woolsorter's  disease.'  The  mortality  of  the  former 
has  been  greatly  reduced  by  serum  therapy. 
Woolsorter's  disease  is  almost  invariably  fatal. 

Pathology, — The  infection  of  the  skin  occurs 
through  abrasions  or  from  bites  of  insects.  A  pustule 
or  carbuncle  results.  The  papillary  layer  and  the 
corium  become  infiltrated  with  inflammatory  cells, 
exudate,  and  extravasated  blood.  In  the  inflamed 
tissues  are  many  anthrax  bacilli.  The  cells  of  the 
overlying  epidermis  undergo  lysis,  with  the  conse- 
quent formation  of  blebs.  If  not  checked  the  infec- 
tion spreads  and  bacilli  make  their  way  into  the 
circulation,  producing  generalised  infection  and 
death. 

Bacteriology, — The  anthrax  bacillus  is  5 — 10  ^  x 
I — 1*5  Gram-positive  and  non-motile.  According 
to  Besson  and  Hutchens,  the  ends  of  the  bacilli 
seen  under  a  high  magnification  show  a  ragged  or 
sinuous  rather  than  straight  edge,  as  though  the 
bacillus  had  been  roughly  broken.  This,  they  say, 
is  quite  characteristic.  Under  suitable  conditions 
the  microbe  produces  a  central  spore.  It  is  aerobic 
and  grows  well  on  ordinary  media. 

164 


The  Skin. 


Immunity. — Local  immunity  is  marked  ;  the  skin 
is  more  highly  resistant  than  the  lungs.  Serum  of 
immunised  animals  contains  immune-body,  which, 
when  activated,  has  a  bactericidal  effect  and  leads 
to  effective  ingestion  and  digestion  by  phagocytes. 
It  also  contains  a  certain  amount  of  antitoxin, 
probably  anti-endotoxin.  Marmier  has  isolated  a 
toxin  which  may  either  be  an  exotoxin  or  an  endo- 
toxin liberated  by  lysis  of  the  bacilli.  The  filtered 
blood  of  infected  animals  appears  to  be  toxic.  In 
human  beings  one  attack,  if  recovered  from, 
immunises. 

The  isolation  of  morphologically  characteristic 
bacilli  from  a  characteristic  lesion  is  sufficient  for 
practical  diagnostic  purposes.  If  a  septicaemia  is 
present  the  microbe  can  be  isolated  from  the  blood 
and  urine. 

Prophylaxis. — Pasteur  immunised  sheep  and 
cattle  by  two  inoculations.  In  Pasteur's  method  the 
bacilli  are  alive  but  are  attenuated  in  virulence  by 
being  grown  at  42°  C. — in  the  case  of  the  first 
vaccine  for  twenty-four  days,  in  the  case  of  the 
second  vaccine  for  fourteen  days.  A  certain  per- 
centage of  animals  are  killed  by  this  method.  Larger 
doses  of  a  killed  vaccine  would  probably  be  suffi- 
ciently effective,  and  would  not  kill  any  animal. 
Undoubtedly,  workers  engaged  with  hides  and  wool, 
especially  the  latter,  since  woolsorter's  disease  is 
always  fatal,  should  receive  prophylactic  inocula- 
tion with  a  killed  vaccine. 

Treatment. — Very  efficient  sera,  such  as  Sclavo's, 
are  to  be  had  commercially  for  the  treatment  of  the 

165 


Therapeutic  Immunisation. 


disease.  Forty  c.c.  should  be  given  at  once  and 
repeated  if  necessary.  There  is  frequently  a  sharp 
rise  of  temperature  following  the  injection,  but  it 
soon  subsides.  If  any  anaphylactic  symptoms  appear 
they  can  be  controlled  with  pituitrin  in  i  c.c.  doses. 

Seborrhcea,  Comedones,  and  Acne.— These  con- 
ditions are  produced  by  overaction  of  the  sebaceous 
glands  of  the  skin  due  to  infection  with  the  acne 
bacillus. 

Pathology. — In  seborrhcea  the  gland  swells  and 
the  increased  secretion  (sebaceous  matter  and 
desquamated  cells)  dries  on  the  surface  (5.  sicca, 
dandruff),  or  when  more  profuse  leads  to  a  greasj^ 
condition  of  the  skin  (S.  oleosa).  The  nutrition  of  the 
hair  root  is  frequently  interfered  with,  with  conse- 
quent falling  out  of  the  hair. 

In  comedones  the  secretion  becomes  dried  at  the 
orifice  of  the  gland,  where  it  forms  a  plug  which 
becomes  dark  in  colour  owing  to  admixture  with 
dirt  and,  possibly,  with  a  special  pigment. 

In  acne  the  blocked  gland  becomes  distended, 
forming  a  papule  which  may  become  red  from 
hypera^mia  and  periglandular  invasion  with  inflam- 
matory cells  [Acne  simplex).  If  the  papule  then 
becomes  infected  with  staphylococci  suppuration 
usually  results  {Acne  pustulosa).  The  suppuration 
frequently  spreads  to  the  subcutaneous  tissues, 
considerable  pockets  of  pus  resulting.  Chronic 
inflammation  often  leads  to  great  pitting  and 
fibrosis  of  the  skin. 

Bacteriology, — In  seborrhcea  and  comedones 
squeezing  of  the  skin  produces  worm-like  masses  of 

l66 


The  Skin. 


greasy  material.  Staining  of  this  material  shows 
large  numbers  of  short  Gram- positive  acne  bacilli, 
which  can  be  grown  by  culturing  on  +  30  agar  anaero- 
bically.  The  colonies  thus  grown,  which  take  ten 
to  fourteen  days  to  become  characteristic,  are  buff- 
coloured  round  colonies,  the  colouring  being  deeper 
in  the  centre,  where  the  colony  is  characteristically 
heaped  up.  I  believe  the  bacillus  exists  in  both  a 
coccal  and  bacillary  form,  for  if  the  cultures  are  taken 
out  of  the  anaerobic  chamber  after  a  fortnight  and 
grown  aerobically  each  colony  (consisting  of  bacilli) 
becomes  surrounded  by  a  halo  of  Gram-positive 
cocci  indistinguishable  from  staphylococci. 

Further,  by  growing  on  different  media  anaerobi- 
cally  I  have  been  able  to  turn  the  coccal  form  into 
the  bacillary  form  and  this  back  again  into  a  coccal 
form.  The  media  used  (a  +  10  glucose  agar  and  a 
serum  medium)  were  equally  suitable  for  growing 
ordinary  staphylococci. 

In  Acne  ptistulosa  staphylococci  are  always  present 
with  the  acne  bacilli. 

Treatment. — Seborrhoea  and  comedones  can  be 
treated  by  acne  bacillus  vaccine  alone,  but  if  there 
are  any  pustules  a  staphylococcus  vaccine  must  be 
used  as  well.  The  initial  dose  of  each  is  100  million 
and  the  series  100  +  100,  200  +  200,  400  +  400, 
600  +  600,  800  -f  800,  1,000  +  1,000,  1,500  + 
1,500,  2,000  +  2,000,  and  so  on  up  to,  at  least, 
5,000  million  +  5, 000  million.  In  old-standing  cases 
very  large  doses  up  to,  perhaps,  30,000  million  -f 
30,000  million  may  have  to  be  attained  before  the 
patient  is  permanently  well. 

167 


Therapeutic  Immunisation. 


Chronic  intestinal  infection  is  frequently  a  predis- 
posing cause  and  must  be  suitably  treated  if  present. 

Ethereal  antiseptic  soap  is  the  best  thing  to  wash 
the  skin  with.  Comedones  and  acne  pustules  ought 
to  be  squeezed  out  or  evacuated  as  they  appear. 

FuRUNCULOSis.' — Boils  and  carbuncles  are  usually 
due  to  staphylococcal  infections,  the  infection 
starting,  as  a  rule,  in  the  sweat  glands,  sebaceous 
glands  or  hair  folUcles. 

Pathology, — In  generalised  furunculosis  the  staphy- 
lococci are  circulating  in  the  blood ;  in  other  cases 
they  may  be  rubbed  into  the  skin.  In  boils  there  is 
one  focus  of  infection,  while  carbuncles  have  several 
centres  which  become  confluent.  The  infection 
produces  necrosis  of  a  mass  of  tissue  which  is  sur- 
rounded by  an  area  of  acute  inflammation;  the 
central  slough  becomes  surrounded  by  pus,  which 
burrows  towards  the  surface,  where  it  discharges. 
The  inflammation  spreads  beyond  the  skin  into 
the  subcutaneous  tissues. 

Bacteriology, — Furunculosis  is  caused  by  Staphy- 
lococcus aureus  as  a  rule,  sometimes  by  alhus  or 
citreus  ;  rarely  by  other  microbes,  such  as  strepto- 
cocci. When  making  the  culture  it  is  well  to  take 
the  specimens  from  the  granulation  tissue  wall  after 
evacuating  the  pus. 

Treatment, — Stock  polyvalent  vaccines  often  do 
quite  well  in  furunculosis  and  may  be  used  pending 
the  making  of  an  autogenous  vaccine.  In  recent 
cases  a  course  of  vaccine  consisting  of  lOO,  200,  400, 
600,  800,  1,000,  1,500,  2,000  million  will  generally 
be  sufficient.  In  chronic  cases  it  may  be  necessary  to 

168 


The  Skin. 


attain  a  dose  of  10,000  million  or  more.  It  is  always 
necessary  to  inquire  into  the  state  of  the  alimentary 
canal  and  to  search  for  a  focus  of  infection  in  the 
upper  ahmentary  and  respiratory  tract. 

If  the  infecting  microbe  is  a  streptococcus  the 
series  10,  20,  40,  60,  80, 100,  150,  200  million  or  more 
will  be  generally  found  suitable. 

The  intervals  between  the  doses  may  be  usually 
four  to  six  days  at  first  in  staphylococcus  infections, 
increasing  the  intervals  as  the  dose  gets  larger. 
After  4,000  milHon  the  intervals  should  be  ten  to 
fourteen  days. 

Sycosis  is  caused  by  an  infection  of  the  hair 
foUicles  and  perifoUicular  tissues. 

Pathology, — The  inflammation  starts  in  the  peri- 
follicular tissue  and  spreads  into  the  hair  follicle, 
the  pus  exuding  from  the  mouth  of  the  follicle 
round  the  hair.  The  centres  of  infection  become 
confluent  and  a  crust  of  dried  pus  and  desquamated 
cells  forms,  underneath  which  is  a  granulating 
surface.  Except  in  bad  cases  the  hair  follicle  is  not 
destroyed. 

Bacteriology, — The  disease  is,  as  a  rule,  caused  by 
the  Staphylococcus  aureus,  which  is  easily  isolated 
from  the  pus.  The  hair  roots  should  be  examined 
to  make  sure  that  ringworm  is  not  present. 

Treatment, — The  disease  heals  up  readily  with  an 
autogenous  staphylococcus  vaccine,  the  series  being 
100,  200,  400,  600,  800,  1,000,  1,500,  2,000,  3,000, 
4,000  million  or  more.  As  a  rule  intervals  of  six 
days  should  be  left  between  the  earlier  doses, 
increased  to  ten  days  between  the  larger. 

169 


Therapeutic  Immunisation. 


Impetigo  is  an  infection  of  the  skin  produced 
by  staphylococci ;  sometimes  streptococci  are  said 
to  be  the  cause  ;  I  have  never  found  them  in  the 
disease.  The  disease  occurs  in  epidemics  and 
spreads  by  contact,  towels,  etc.,  from  one  area  of 
the  skin  to  another  and  from  one  person  to  another. 
The  areas  are,  as  a  rule,  small,  and  there  is  little 
infiltration.  When  the  areas  are  large  and  there  is 
more  infiltration,  the  condition  is  known  as  ecthyma. 
Closely  related  to  this  disease  is  pemphigus  neona- 
torum, also  caused  by  staphylococci,  which  often 
occurs  in  epidemics. 

Pathology, — The  inflammation  starts  in  the  dermis. 
The  overlying  cells  of  the  deeper  layers  of  the 
epidermis  undergo  colliquative  necrosis,  so  that  a 
bleb  forms ;  this  bursts  through  the  horny  layers 
and  the  secretion  dries  into  a  yellow  crust.  In 
pemphigus  the  microbe  is  in  the  circulation,  the 
blebs  in  the  skin  being  focal  manifestations. 

Treatment, — In  ordinary  local  treatment  (a  strong 
iodine  ointment  or  liq.  iodi  fort,  being  the  best),  the 
condition  can  be  cleared  up  with  an  autogenous 
vaccine,  the  series  being  lOO,  200,  400,  600,  800, 
1,000  million,  or  more  if  necessary,  of  the  staphylo- 
coccus vaccine.  In  infants  with  pemphigus  the 
initial  dose  should  be  25  miUion,  followed  by  50  and 
100  million. 

Eczema  is  a  general  term  for  dermatitis  which 
may  have  many  primary  causes.  Staphylococci  are 
generally  found  in  the  lesions  and  the  infection  with 
them  may  be  the  primary  cause,  but  frequently  the 
resistance  of  the  skin  is  lowered  first  by  external 

170 


The  Skin. 


irritation,  chemical,  thermal.  X-rays,  or  mechanical 
or  chronic  poisoning  or  infection  from  the  gastro- 
intestinal tract,  as  in  gout. 

Pathology. — The  inflammation  generally  starts  in 
a  papilla,  which  shows  the  usual  signs  of  inflamma- 
tion (papular  eczema).  This  may  work  downwards 
into  the  chorium  and  spread  so  that  extensive  areas 
may  be  involved.  The  overlying  layer  of  cells  of  the 
epidermis  becomes  hypertrophied.  This  may  lead 
to  over-keratinisation  with  the  formation  of  scales, 
or  the  Malpighian  cells  may  undergo  lysis  with  the 
formation  of  bullae ;  the  shedding  of  the  cuticle  over 
these  leaves  a  weeping  surface.  This  weeping  sur- 
face may  be  so  extensive  as  to  cover  the  whole  body 
(weeping  eczema). 

Bacteriology, — The  infecting  microbe  can  be  easily 
isolated  from  pustules  or  bullae,  or  a  weeping  surface. 
In  dry  erythematous  or  scaly  eczema  the  best  way 
to  obtain  the  microbe  is  to  make  an  artificial  bulla 
by  means  of  blistering  fluid  and  obtain  the  culture 
from  the  raw  base  of  this.  Much  the  most  common 
microbe  found  is  the  staphylococcus,  but  it  is  by 
no  means  the  only  cause.  I  have  isolated  in  one  case 
streptococci  and  Gram-negative  bacilli  of  the  B, 
proteus  group ;  later  during  a  relapse  Staphylococcus 
aureus  was  isolated  in  pure  culture  from  this  case,  the 
other  microbes  having  disappeared  after  a  few  doses 
of  vaccine. 

Treatment, — Autogenous  staphylococcus  vaccine, 
as  a  rule,  gives  very  good  results.  In  chronic  case 
very  large  doses  must  be  attained.  The  initial  dose 
is  100  million  and  the  series  loo,  200,  400.  600,  800, 

171 


Therapeutic  Immunisation. 


1,000,  1,500,  2,000,  and  so  on,  up  to  30,000  million 
or  more  if  necessary.  If  the  patient  has  a  chronic 
alimentary  infection,  as  in  rheumatism  and  gout,  it 
must  be  treated  suitably.  Of  course,  chemical  or 
other  irritation  must  be  removed.  If  streptococci 
are  the  cause,  or  other  microbe,  the  initial  dose  is 
2| — 5  miUion,  and  the  series  2|,  5,  7|-,  10,  15,  20,  up 
to  500  miUion  or  more. 


172 


CHAPTER  XL 


VASCULAR  SYSTEM,  LYMPHATIC  SYSTEM,  NERVOUS 
SYSTEM,  EYE  AND  EAR. 

Microbial  infections  of  the  vascular  system  are 
usually  associated  with  some  focus  of  a  disease  from 
which  the  blood  stream  becomes  infected,  either  by 
direct  invasion  through  the  walls  of  a  blood  vessel  or 
via  the  lymphatics.  Most  of  these  sources  of  infec- 
tion have  already  been  noticed,  e.g.,  the  ent ericas, 
rheumatic  fever,  puerperal  fever.  In  other  cases  the 
infection  seems  to  be  carried  into  the  interior 
through  apparently  intact  mucous  membrane  by 
phagocytes,  which  the  ingested  microbes  eventually 
kill,  or  into  the  lymph  stream,  for  instance,  through 
the  stomata  in  the  alveoli  of  the  lungs.  It  may  be 
that  there  is  always  some  local  inflammatory 
change  insufficient  to  give  rise  to  symptoms. 

A  good  instance  of  a  septicaemia  without  an 
apparent  focus  of  infection  is  Mediterranean  fever, 
which  may  suitably  be  considered  here. 

Undulent  or  Mediterranean  Fever  is  caused 
by  a  minute  bacillus,  the  B,  Melitensis.  Typically, 
the  temperature  is  undulating,  rising  steadily  to  a 
maximum,  then  falKng  by  lysis  to  99  deg.  F.  or  less 
for  some  days,  then  rising  again  as  before.  Severe 
perspirations  are  a  feature  of  the  symptoms.  This 
sequence  of  events  sometimes  continues  with  ordi- 
nary expectant  treatment  for  months,  even  for  a  year 

173 


Therapeutic  Immunisation. 


or  two.  In  the  worst  cases,  which  are  frequently 
fatal,  the  patient  is  in  a  severe  '  typhoid  '  state 
with  a  continuously  high  evening  temperature  and 
delirium.  In  other,  abortive,  cases  there  is  only 
one  temperature  period. 

Pathology, — There  are  no  particular  pathological 
changes  to  be  described,  the  spleen  and  liver  are 
enlarged  and  the  microbe  can  be  isolated  from  them 
by  puncture  during  life,  as  it  can  from  the  blood 
and  urine  and  also  from  the  kidneys  post  mortem. 

Bacteriology, — The  B,  Melitensis,  or,  as  it  is  usually 
called,  the  Micrococcus  Melitensis,  is  in  its  coccal 
form  about  3  in  diameter  ;  if  grown  on  suitable 
media  it  is  in  appearance  and  size  identical  with  the 
influenza  or  whooping-cough  bacillus  and,  as  in  the 
case  of  these  microbes,  occasional  longer  forms  are 
seen.  It  is  aerobic  and  Gram- negative.  It  grows 
excellently  on  fresh  human  blood-agar.  A  catheter 
specimen  of  urine  is  centrifuged  and  the  deposit 
sown  thickty  on  the  slopes.  During  the  fever, 
especially  during  the  rising  period,  the  microbe  can, 
usually,  be  isolated  from  the  blood;  lo  c.c.  of  blood 
taken  from  an  arm  vein  should  be  put  into  50  c.c.  of 
broth  and  after  some  days  subcultures  made  on 
blood-agar.  Subculturing  may  have  to  be  con- 
tinued for  ten  days  or  more  before  colonies  appear. 
As  with  other  delicate  microbes,  the  media  must  be 
made  from  fresh  meat  and  not  heated  above  100 
deg.  C.  in  their  manufacture. 

The  colonies  when  they  appear  first  are  translucent 
and  I — 3  mm.  in  diameter.  Afterwards  they 
become  raised  and  white,  and,  as  they  become  older, 

174 


Vascular  System. 


brown  in  appearance.  The  microbe  will  not  liquefy 
gelatine  and  will  not  grow  at  22  deg.  C. 

Prophylaxis. — The  prevention  of  the  disease  is 
very  simple  and  consists  in  not  drinking  goat's 
milk  unless  it  is  sterilised.  As  the  poorer  classes 
cannot  be  persuaded  to  do  this,  preventive  inocula- 
tion would  probably  be  effective.  The  doses  would 
have  to  be  large,  500  to  2,000  million  at  least. 

Treatment. — No  effective  serum  has  been  pro- 
duced. Vaccine  therapy  is  very  effective.  In 
ordinary  undulent  cases  the  initial  dose  is  50  million, 
and  the  subsequent  series  100,  150,  200,  300,  500, 
750,  1,000  million  and  higher,  given  at  suitable 
intervals.  In  '  typhoid '  cases  the  initial  dose 
should  not  be  more  than  25  million. 

If  possible  the  vaccine  should  be  autogenous  and 
grown  on  the  patient's  blood. 

Heart  Disease. — Infections  of  the  heart  are 
always  associated  with  septicaemias  and  occur  in 
such  diseases  as  rheumatic  fever,  scarlet  fever,  pneu- 
monia and  gonorrhoeal  septicaemia.  By  far  the  most 
common  causes  of  endocarditis,  pericarditis  and 
myocarditis  are  microbes  belonging  to  the  pneumo- 
streptococcal  group,  to  which  the  microbes  causing 
scarlet  fever,  rheumatic  fever  and  pneumonia  belong. 

Pathology. — Pericarditis. — The  pericardium  may 
be  infected  through  the  blood  stream,  as  already 
mentioned,  or  by  extension  of  infection  from  neigh- 
bouring organs,  such  as  the  heart,  lungs,  pleura, 
mediastinal  glands,  or  through  the  diaphragm  from 
abdominal  infections. 

The  first  histological  changes  are  hyperaemia  with 

175 


Therapeutic  Immunisation. 


increased  exudate  of  fluid  having  a  large  amount  of 
fibrin,  which  becomes  deposited  on  the  surface,  and 
migration  of  leucocytes.  The  endothelial  cells 
become  cuboidal  and  desquamate  or  bud  off.  The 
causative  microbes  are  seen  in  the  cellulo-fibrinous 
mass  or  phagocyted  in  the  cells.  If  these  microbes 
are  pyogenic  they  produce  suppuration,  if  their  toxins 
produce  lysis  of  the  capillary  cells  the  effusion  is 
haemorrhagic.  If  there  is  little  effusion  the  peri- 
carditis is  '  dry.'  If  the  stomata  are  blocked  with 
fibrin  plugs  the  effusion  may  be  very  large.  The 
fibrin  may  become  organised  and  adhesions  form, 
or  the  visceral  and  parietal  layers  may  become 
firmly  united  in  this  way.  Sometimes  the  whole 
process  ends  in  calcification. 

In  MYOCARDms  the  infection  either  spreads  into 
the  muscle  from  the  pericardium  or  endocardium,  or 
is  carried  to  it  by  the  blood  stream. 

The  earliest  change  is  swelling  of  the  muscle  cells 
with  obscuring  of  the  nuclei  (cloudy  swelling) ;  this 
is  accompanied  by  hyperaemia,  migration  of  leuco- 
cytes into  the  connective  tissue  and  proliferation  of 
connective  tissue  cells.  In  pyogenic  septicaemias 
small  abscesses  result.  If  the  infection  is  overcome 
the  changes  may  completely  resolve.  In  other  cases 
organisation  of  the  exudate  results,  with  consequent 
increase  of  fibrous  tissue,  some  of  the  muscle  fibres 
undergoing  fatty  degeneration.  In  some  non-pyo- 
genic  infections,  e.g,,  pneumonia,  the  muscle  cells 
are  so  poisoned  that  fragmentation  occurs,  with 
consequent  dilatation  of  the  heart,  which  may  be 
so  extreme  that  the  heart  stops  beating. 

176 


Vascular  System. 


Endocarditis. — The  most  common  and  impor- 
tant sites  of  endocarditis  are  the  valves,  and  the 
most  common  parts  of  them  to  be  affected  are  those 
which  are  appHed  together  during  the  closing  of 
them ;  but  any  part  of  the  intima  of  the  heart  may 
be  infected. 

Pathology. — The  processes  are  briefly  as  follows  : 
microbes  are  deposited  on  the  surface,  probably  being 
clasped  on  to  them  from  the  blood  during  the  closure. 
The  endothelial  cells  in  contact  with  the  microbes 
become  cuboidal  and  ingest  the  microbes  and  are 
killed  and  thrown  off.  On  the  denuded  surface 
blood  platelets  are  deposited  and  afterwards  fibrin 
and  leucocytes.  The  subjacent  tissues  react  and 
there  is  proliferation  of  small  round  cells  and 
oedema.  If  the  infection  is  very  virulent  the 
microbes  entangled  in  the  cellulofibrinous  deposit 
destroy  the  subjacent  tissues  and  an  ulcer  results 
which  may  perforate  through  or  destroy  the  whole 
or  a  large  part  of  the  valve.  In  less  virulent  infec- 
tions the  fibrinocellular  deposit  may  attain  large 
proportions  and  become  organised  by  the  ingrowth 
of  fibroblasts  and  capillaries.  This  occurs  early  in 
the  case  of  the  tricuspid  and  mitral  valves,  which 
have  blood-vessels  in  their  proximal  parts ;  later,  in 
the  case  of  the  aortic  and  pulmonary  valves,  which 
have  not. 

When  the  patient  survives  the  valves  become 
distorted  from  contraction  of  the  fibrous  tissue  and 
the  damaged  valves  are  liable  to  become  more 
damaged  from  the  increased  strains  they  have  to 
bear,  with  resulting  increase  of  fibrous  tissue  from 


Therapeutic  Immunisation. 


their  reaction  to  these  strains.  The  valves  are  also 
less  able  to  resist  fresh  infections  if  they  occur,  as 
they  so  commonly  do,  mostly  from  the  primary  focus 
of  infection. 

Prophylaxis  and  Treatment. — Since  the  heart 
valves  once  damaged  can  never  be  restored  to  normal, 
and,  since  once  damaged,  the  sclerosis  is  likely  to 
increase  from  strain  reaction,  it  is  all-important  to 
prevent  the  occurrence  of  infection  by  destroying 
the  primary  foci  likely  to  produce  the  septicaemia 
by  vaccines  and  surgical  measures ;  and,  if 
septicaemia  occurs,  to  reduce  its  activities  to  a  mini- 
mum by  means  of  the  methods  already  described  for 
scarlet  fever  and  rheumatic  fever. 

Infections  of  the  Blood-vessels. — There  will 
be  no  necessity  to  discuss  these  separately,  as  those 
which  occur  as  part  of  a  septicaemia  have  the 
same  etiology  and  treatment  as  heart  disease  and 
those  which  are  produced  by  spread  of  disease 
from  surrounding  infection  are  only  of  separate 
interest,  since  they  may  lead  to  septicaemia  or 
pyaemia. 

There  is  one  condition  of  the  arteries,  how- 
ever, about  which  a  word  or  two  may  be  said, 
viz.  : — 

Arteriosclerosis. — There  are  several  methods 
by  which  this  condition  may  be  brought  about. 
Leaving  out  syphilis  and  chronic  poisoning,  such  as 
lead  poisoning,  there  can  be  no  doubt  that  acute 
and  chronic  septicaemia  can  produce  this  condition. 
Such  septicaemias  and  toxaemias  occur  in  gout  and 
rheumatism,  where,  ' -not   only  is  there  chronic 

178 


Vascular  System. 


bacteriaemia,  but  also  chronic  intoxication  produced 
by  abnormal  intestinal  and  tissue  metabolism; 
while  also  the  balance  between  the  various  internal 
secretions  is  upset  and  the  quality  of  them  sub- 
normal or  abnormal. 

Pathology. — The  first  change  when  a  strain  is 
put  on  the  vessel  wall  is  a  thickening  of  the  muscle 
coat;  there  is  next  a  subendothelial  collection  of 
small  round  cells  produced  by  reaction  of  the  connec- 
tive tissues  in  this  situation.  If  the  cause  of  this 
hypertrophy  is  not  removed  fibroblasts  develop 
in  the  intima  and  muscular  coats,  and  there  is 
also  an  increase  of  the  connective  tissue  of  the 
adventitia.  The  last  state  is  fatty  degeneration 
and  the  deposit  of  lime  salts,  turning  the  vessel 
into  a  rigid  tube. 

The  extent  of  recovery  that  is  possible  in  an 
hypertrophied  artery  can  best  be  reaKsed  by  remem- 
bering what  happens  to  the  arteries  after  parturition. 
I  have  seen  the  same  thing  occur  in  a  case  of  very 
severe  exophthalmic  goitre  in  a  man  in  whom  there 
was  a  large  pulsating  artery  on  the  surface  of  each 
greatly  enlarged  lateral  lobe.  Under  treatment  with, 
first,  adrenalin  and  then  pituitrin,  the  enlargement 
of  the  thyroid  completely  disappeared,  leaving  the 
hypertrophied  arteries  running  a  visible  and  tortuous 
course  over  where  the  enlarged  lateral  lobes  had  been. 
After  some  months  these  completely  disappeared. 
In  another  case,  which  had  been  diagnosed  as  a  case 
of  cardio-  and  arteriosclerosis  in  a  man  of  55, 
the  retinal  arteries  were  tortuous,  had  the  typical 
silver  wire  appearance  and  the  veins  were  obliterated 


Therapeutic  Immunisation. 


where  they  passed  under  them.  After  six  months  of 
treatment  they  were  restored  to  an  appearance 
normal  for  a  man  of  the  patient's  age.  So  that  a 
large  degree  of  recovery  of  thickened  arteries  is 
possible  and,  unless  they  are  calcified,  worth  trying 
for.  The  primary  cause  in  some  cases  is  not  an 
intoxication,  but  a  neurosis. 

Treatment  must  aim  at  (i)  a  permanent  reduc- 
tion of  high  blood  pressure  ;  (2)  restoration  of  the 
salt  content  of  the  blood ;  (3)  removal  of  the 
fundamental  toxaemia. 

Thyroid  extract  is  by  far  the  best  way  of  reducing 
blood  pressure.  It  should  be  increased  to  the 
patient's  physiological  limits  and  should  be  kept  up 
for  a  long  time.  The  salt  content  is  restored  by 
giving  the  salts  of  Trunecek's  serum,  which  may 
conveniently  be  given  in  tablet  form.  Each  tablet 
has  the  following  formula : — 

Sod.  chlor.,  '4  gramme. 

Sod.  sulphat,  '04  ,, 

Sod.  cart.,  "016  ,, 

Sod.  phosph.,  '012  „ 

Mag.  phosph.,  '016  ,, 

Calc.glycerophosph., -012  „ 

Two  should  be  given  three  times  a  day  with  ten 
ounces  of  water. 

The  toxaemia  should  be  cleared  up  in  the  way 
already  described  in  the  chapter  on  intestinal  infec- 
tions. Even  in  neurasthenic  cases  the  intestinal 
infection  comes  to  play  an  important  part  as  a 
factor  in  the  vicious  circle. 

180 


Lymphatic  System. 


Lymphatic  Glands. 

Lymphatic  glands  are  usually  infected  through 
the  lymphatics  coming  from  an  infected  area  or  from 
a  place  where  microbes  get  carried  into  the  interior 
by  phagocytes,  which  place  is  often  a  collection  of 
lymphoid  cells  close  to  the  surface  of  a  mucous 
membrane,  such  as  in  the  tonsils,  respiratory 
passages  and  intestinal  tract.  The  glands  are  places 
where  the  microbes  are  filtered  off  and  so  prevented 
from  getting  into  the  system,  for  in  them  there  are 
particular  facilities  for  phagocytosis.  If  their  resist- 
ance is  overcome  inflammation  of  them  results  or 
the  infection  may  be  carried  on  into  the  vascular 
system. 

The  lesions  produced  in  connection  with  other 
areas  of  infection  need  not  be  separately  considered. 

Since  the  usual  type  of  plague  is  associated  with 
enlargement  of  the  lymphatic  glands  this  disease 
may  be  briefly  considered  here. 

Plague  is  caused  by  the  Bacillus  pestis  and  is  a 
septicaemia,  sometimes  without  focal  manifestations 
but  generally  with  focal  lesions  in  the  lymphatic 
glands  (bubonic  plague),  more  rarely  in  the  lungs 
(pneumonic  plague)  as  in  the  terrible  Manchurian 
epidemic. 

Pathology, — In  bubonic  plague  the  microbe  is 
inoculated  into  the  skin  by  fleas  generally  from 
infected  rats.  The  most  common  agent  is  the  rat- 
flea  {Xenopsylus  or  Pulex  cheopis).  But  infection 
from  man  to  man  can  take  place  by  the  human 
flea  [Pulex  irritans)  or  bed-bugs  [Cimex  lectularius) . 

i8i 


Therapeutic  Immunisation. 


The  glands  receiving  the  lymphatics  from  the 
area  of  skin  first  infected,  where  a  haemorrhagic 
oedema  occurs,  are  naturally  the  first  to  enlarge. 
In  50  per  cent,  of  cases  these  are  the  inguinal  glands, 
in  25  per  cent,  the  axillary  glands.  Rapidly  the 
other  collections  of  glands  are  infected,  e.g.,  the 
glands  at  the  roots  of  the  lungs,  those  of  the  mesen- 
tery and  of  the  pharynx.  The  glands  become 
enlarged  and  haemorrhagic,  the  surrounding  tissues 
show  haemorrhagic  oedema.  The  blood-vessels  and 
lymphatics  of  the  glands  are  engorged  and  full  of 
bacilli  and  desquamated  and  budded  off  endothelial 
cells  containing  the  microbes.  The  lymphoid  cells 
also  proliferate  and  a  number  of  large  cells  con- 
taining coarse  basophile  granules  are  present ;  a  few 
plasma  cells  are  seen,  but  very  few  polynuclear  cells. 
In  abortive  cases  {pestis  minor)  the  glands  undergo 
resolution.  As  a  rule  necrosis  takes  place,  the  cells 
undergoing  degeneration  and  the  whole  either 
becoming  like  lard  or  a  semi-fluid  gummy  material. 
Haemorrhages  are  common  owing  to  lysis  of  the 
endothelial  cells  of  the  capillaries.  Haemorrhages 
from  the  same  cause  are  found  in  the  skin  and 
internal  organs,  such  as  the  liver  and  spleen,  which 
also  contain  areas  of  necrosis. 

In  pneumonic  plague  the  lungs  are  primarily 
infected,  the  infection  being  conveyed  by  atomised 
droplets  of  sputum  from  one  case  to  another. 
Pneumonia  sometimes  occurs  as  a  secondary  focus  in 
bubonic  plague,  and  haemorrhages  from  the  lungs 
are  not  uncommon.  There  is  no  special  pathological 
histology  of  the  lungs  requiring  notice. 

182 


Lymphatic  System. 


Bacteriology, — The  B,  pestis  is,  when  seen  in 
smears  made  from  material  withdrawn  by  puncture 
of  the  enlarged  glands  or  otherwise,  a  short,  fat. 
Gram-negative  bacillus,  2 /x  X  i  /x,  with  rounded  ends. 
When  stained  with  weak  aniline  dyes  the  ends  stain 
more  deeply  than  the  middle.  By  varying  the 
environment,  as  in  the  case  with  so  many  microbes, 
S.  Roland  has  produced  forms  resembling  micro- 
cocci, streptococci,  bacteria,  streptothrices  and 
mould  fungi. 

In  broth  the  coccobacillus  often  forms  chains,  the 
masses  fall  to  the  bottom,  leaving  a  clear  supernatant 
fluid  with  sometimes  a  pellicle  on  the  surface.  If  a 
layer  of  oil  has  been  placed  on  the  surface  the 
microbes  adhere  to  its  under-surface  and  grow  down 
into  the  broth  in  the  form  of  stalactite. 

The  bacillus  grows  as  rounded  white  colonies  on 
agar,  glycerine  agar  and  serum. 

When  grown  for  vaccine  purposes  fresh  human 
blood-agar  should  be  used. 

The  toxin  of  the  microbe  is  probably  an  endo- 
toxin, which  may  be  liberated  by  autolysis  into  fluid 
culture  media.  Roland  has  isolated  a  toxic  nucleo- 
protein. 

Immunising  sera,  such  as  Yersin's,  produced  in 
horses  by  inoculating  with  gradually  increasing 
doses  of  dead  vaccine,  followed  by  injections  of 
suspensions  of  live  bacilli,  are  powerfully  bacterio- 
lytic. Lustig  and  Rowland  have  prepared  antitoxic 
sera,  the  latter  by  injecting  his  toxic  nucleoprotein. 
Any  antibacterial  serum  cannot  be  of  much  use 
unless  it  contains  antitoxins  in  sufficient  amounts. 

183 


Therapeutic  Immunisation. 


Any  recovery  under  unaided  conditions  must  be 
chiefly  due  to  effective  phagocytosis. 

Prophylaxis. — The  case  incidence  and  case  mor- 
taUty  of  bubonic  plague  have  been  greatly  reduced 
by  preventive  inoculation.  In  the  Punjab  in 
1902 — 1903  the  case  incidence  amongst  the  unin- 
oculated  inhabitants  was  7*7  per  cent.,  and  the  case 
mortality  60* i  per  cent.,  while  the  figures  amongst 
the  inoculated  were  i'8  per  cent,  and  23*9  per  cent, 
respectively.  Haffkine's  vaccine  has  been  most 
largely  used  for  the  purpose.  It  consists  of  broth 
cultures  grown  for  two  months  and  sterilised  by 
heating  to  65  deg.  C. ;  2*5 — 5  c.c.  are  given  sub- 
cutaneously.  The  immunity  lasts  on  an  average 
twelve  to  eighteen  months.  The  negative  phase 
lasts,  as  a  rule,  not  more  than  twenty-four  hours. 
If  there  is  any  suspicion  that  the  patient  may  have 
already  become  infected,  a  first  dose  of  2*5  c.c.  com- 
bined with  10  c.c.  of  Yersin's  or  other  serum  should 
be  given  as  a  first  dose  and  5  c.c.  of  vaccine  given 
after  a  suitable  interval.  Rowland  has  produced 
very  good  prophylactic  results  in  rats  by  the  injection 
of  one  minute  dose  ('02 — 'oooi  mg.)  of  his  nucleo- 
protein  extract ;  10  c.c.  of  Yersin's  serum  protects, 
as  a  rule,  for  ten  days. 

Treatment. — No  treatment,  prophylactic  or  cura- 
tive, is  of  the  sUghtest  use  in  pneumonic  plague. 

Serum  therapy  appears  to  have  some  effect  in  the 
treatment  of  bubonic  plague.  Large  doses  must  be 
used  and  frequently  repeated  until  the  temperature 
is  normal  and  for  some  days  after.  Yersin's  serum 
obtained  from  horses,  in  the  usual  way  has  been 

184 


Lymphatic  System. 


mostly  used  ;  lOO  c.c.  should  be  given  at  once, 
intravenously,  and  40 — 60  c.c,  subcutaneously  or 
intramuscularly  within  twenty-four  hours,  and  this 
dose  repeated  once  or  twice  a  day  as  long  as  is 
necessary. 

Rowland  has  protected  rats  with  a  serum  pre- 
pared from  horses  by  giving  them  an  ascending 
series  of  doses  ('Oi — 240  mg.)  of  his  nucleoprotein. 
Control  experiments  with  Yersin's  serum  failed. 
As  it  is  essential  in  dealing  with  an  easily  lysed 
microbe  like  the  plague  bacillus  that  sufficient 
anti-endotoxin  should  be  present  in  the  serum,  it 
is  probable  that  Rowland's  serum  will  be  found 
more  efficient  than  those  prepared  in  the  ordinary 
way.  Rowland  records  eighty-seven  cases  of  plague 
treated  with  vaccines.  Of  these  all  forty-three 
septicaemic  cases  died,  while  the  forty-four  non- 
septicaemic  cases  recovered. 

F.  P.  Connor  has  treated  three  cases  of  plague, 
one  very  severe,  by  repeated  intravenous  injections 
of  7  min.  of  tincture  of  iodine  in  i  dr.  of  distilled 
water.  All  three  recovered. 

Lymphadenoma  (Hodgkin's  Disease). — Several 
observers  have  isolated  a  diphtheroid  bacillus  from 
the  lymphatic  glands  and  in  acute  cases  from  the 
the  blood  in  cases  of  this  disease.  Vaccines  pre- 
pared from  this  microbe  have  given  encouraging 
results  in  some  cases. 

There  are  no  infections  of  the  other  ductless 
glands  peculiar  to  them.  They  are  involved  in 
septicaemias,  but  their  treatment  does  not  require 
separate  mention. 

185 


Therapeutic  Immunisation. 


Nervous  System, 

With  few  exceptions,  such  as  acute  infections, 
for  instance,  cerebrospinal  meningitis  and  meningitis 
occurring  as  complications  of  other  infections,  tuber- 
cular disease  and  syphilitic  infections,  little  has  been 
done  to  elucidate  the  cause  of  such  diseases  of  the 
central  nervous  system  as  disseminated  sclerosis, 
acute  myelitis  and  the  various  other  paralyses,  and 
so  on.  It  is  interesting  in  this  connection  that 
Cruickshank  has  found  that  about  25  per  cent,  of 
the  inmates  of  the  Creighton  Institute  were  excreting 
microbes  in  their  urine,  while  acute  mania  has  often 
the  characteristics  of  an  acute  infectious  disease. 

Cerebrospinal  Meningitis. — Epidemic  cerebro- 
spinal meningitis  is  caused  by  the  meningococcus. 
The  disease  appears  to  start  as  an  infection  of  the 
nasopharynx,  a  septicaemia  results,  and  from  these 
microbes  in  the  circulation  the  central  nervous 
system  becomes  infected.  In  some  cases  the  infection 
of  the  meninges  may  occur  directly  from  the  nasal 
passages. 

Pathology, — The  cerebrospinal  fluid  is  purulent, 
containing  numerous,  mostly  polynuclear,  leuco- 
cytes and  fibrin.  The  meninges  show  the  usual 
signs  of  inflammation,  ix,,  distended  blood-vessels 
and  exudation.  The  vessels  of  the  cortex  of  the 
brain  and  cord  are  distended  and  surrounded  by 
aggregations  of  leucocytes.  Many  small  haemor- 
rhages occur  and  sometimes  larger  areas  of  necrosis. 
The  choroid  plexuses  are  inflamed  and  the  ven- 
tricles may  become  distended.    In  chronic  cases 

186 


Nervous  System. 


the  closure  by  inflammatory  processes  of  the 
foramen  of  Majendie  and  the  other  foramina  may 
lead  to  internal  hydrocephalus.  Quite  often  septic 
arthritis  and  less  often  abscesses  due  to  the  meningo- 
coccus occur.   Petechial  spots  are  very  common. 

Bacteriology, — The  Diplococcus  intracellularis  or 
meningococcus  of  Weichselbaum  is  a  Gram-negative 
diplococcus  occurring  frequently  inside  the  poly- 
nuclear  cells  in  the  cerebrospinal  fluid  and  in  the 
pus  from  arthritis.  It  is  very  like  the  gonococcus 
in  appearance,  and  like  it  is  very  particular  as  to 
the  medium  it  grows  on.  Many  special  media  have 
been  advocated  for  its  growth  ;  all  that  is  neces- 
sary is  that  the  medium  should  be  made  from 
fresh  meat,  should  be  accurately  lo  in  reaction 
and  should  contain  about  i  c.c.  of  blood,  preferably 
the  patient's,  to  each  lo  c.c.  of  medium.  The  cere- 
brospinal fluid  should  be  centrifuged  and  the 
cultures,  agar  plates  or  slopes,  made  from  the  deposit. 
A  good  way  also,  if  the  microbes  are  not  very 
numerous,  is  to  add  an  equal  part  of  the  pus  to  broth, 
incubate  overnight  and  then  inoculate  solid  media. 
The  cultures  should  be  made  without  delay  as  the 
organism  soon  dies  out  unless  kept  at  body  tempera- 
ture. If  the  medium  is  suitable  the  microbe  grows 
rapidly,  the  colonies  being  clear  and  regular  in  out- 
Hne  and  may  attain  several  millimetres  in  diameter. 

The  meningococcus  ferments  glucose  and  maltose 
slowly.  It  has  no  action  on  levulose,  saccharose  or 
inulin.  For  all  practical  purposes  a  case  of  menin- 
gitis in  the  cerebrospinal  fluid  from  which  are  seen 
Gram -negative   diplococci  situated  intracellularly 

187 


Therapeutic  Immunisation. 


may  be  taken  as  being  due  to  the  meningococcus, 
pending  a  report  on  the  cultural  and  serological 
characteristics  of  the  microbe  isolated. 

When  the  cultures  are  made  from  nasopharyngeal 
swabs  the  diagnosis  is  not  so  easy,  since  many 
varieties  of  Gram-negative  cocci  can  be  isolated  from 
this  region.  Some  of  these,  such  as  the  Micrococcus 
catarrhalis,  the  Diplococcus  pharyngis  siccus,  and 
the  Micrococcus flavus,  have  colonies  quite  unlike  the 
meningococcus.  But  sugar  reactions  and  agglutina- 
tion tests  will  have  to  be  applied  to  microbes  from 
characteristic  colonies  before  a  definite  diagnosis  can 
be  made.  The  microbe  can  often  be  isolated  from  the 
urine  and  blood.  The  toxin  of  the  microbe  is  an  endo- 
toxin ;  at  least,  no  exotoxin  appears  to  be  formed 
in  vitro.  Immunity  is  produced  by  the  formation 
of  coferment  or  immune-body,  which  enables  the 
phagocytic  cells  to  ingest  and  digest  the  microbe, 
and  of  anti-endotoxin,  which  neutrahses  its  toxin. 
Phagocytosis  is  aided  by  the  agglutinating  functions 
of  antibodies.  In  fact  the  mechanism  of  immunity 
is  quite  typical.  Accompanying  and  secondary 
infections  are  of  frequent  occurrence,  such  as  diph- 
theroid bacilli.  Gram-positive  cocci  and  pneumo- 
cocci. 

Prophylaxis. — Contacts  frequently  carry  the 
microbe  in  the  nasopharynx  and  excrete  them  in 
their  urine  in  some  cases.  Many  nose  washes  have 
been  used  for  these  cases ;  "2  per  cent,  benzoyl 
chloride  in  liquid  paraffin  used  in  an  atomiser  will 
probably  be  found  more  effective  than  most.  All 
contacts—at  any  rate,  all  in  whom  the  microbe  is 

i88 


Nervous  System. 


found — should  receive  prophylactic  inoculation  with 
the  particular  strain  of  microbe ;  the  series  25,  50, 
100,  200  million  will  generally  be  found  effective. 

Treatment, — The  first  essential  is  to  reduce  at  once 
the  tension  of  the  cerebrospinal  fluid  to  normal 
and  then  to  keep  it  there.  No  manometer  is  neces- 
sary ;  when  the  fluid  from  the  puncturing  cannula 
drips  normally  the  cannula  can  be  removed,  or  if 
serum  is  being  used  the  serum  injected.  I  have 
removed  as  much  as  80  c.c.  at  one  time. 

The  serum  treatment  is  that  chiefly  in  vogue.  It 
is  usually  injected  intrathecally  and  the  foot  of  the 
bed  raised  to  facilitate  its  spread  upwards.  Various 
reports  as  to  its  efficacy  have  been  recorded,  giving 
mortalities  varying  from  8 — 40  per  cent,  or  more. 
The  serum  is  evidently  useful  if  it  happens 
to  hit  off  the  strain,  as  is  the  case  with  all  anti- 
bacterial sera.  Quite  as  good  or  better  results  have 
been  reported  from  simple  lumbar  puncture  alone, 
especially  when  efficiently  carried  out. 

In  a  small  series  of  cases  I  have  recovered  five  out 
of  six  cases  with  lumbar  puncture  and  vaccine.  The 
case  that  died  had  been  unconscious  for  four  days 
before  admission.  One  case  that  recovered  had 
chronic  nephritis  with  a  large  amount  of  albumen 
in  the  urine.  My  practice  is  to  do  a  lumbar  puncture 
at  once  and  give  2|  million  of  a  vaccine  made  from 
another  case.  The  patient  is  watched  for  any  slowing 
of  the  pulse ;  if  this  occurs,  puncture  is  at  once  done 
again.  If  there  is  increase  of  symptoms  after  the 
vaccine  the  2|  million  dose  of  autogenous  vaccine  is 
given  after  these  have  passed  off.   If  no  increase 

189 


Therapeutic  Immunisation. 


of  symptoms  or  if  improvement  has  taken  place  the 
autogenous  vaccine  is  given  thirty-six  hours  after 
the  first  dose.  The  series  2-|,  5,  7I,  10,  15,  20  is 
usually  sufficient ;  sometimes  higher  doses  are  neces- 
sary. Unless  the  patient  is  unconscious  I  much 
prefer  to  do  the  puncture  under  light  general 
anaesthesia,  which  prevents  shock  and  relaxes  the 
arching  of  the  back. 

Acute  cerebrospinal  meningitis  produced  by  other 
microbes,  such  as  the  pneumococcus,  are  investi- 
gated and  treated  on  the  same  lines. 

Neuritis. — Inflammation  of  the  nerves  produced 
by  microbes,  apart  from  that  produced  by  direct 
extension,  has  the  same  etiology  and  treatment  as 
other  rheumatic  conditions,  for  instance,  rheumatism 
of  joints  iq^v,). 

Tetanus  is  one  of  the  few  instances  of  disease 
produced  solely  by  an  exotoxin,  for  the  toxin- 
producing  microbes  appear  to  be  entirely  confined 
to  the  wound  into  which  the  tetanus  bacilli  or  their 
spores  have  been  introduced. 

Pathology, — The  wound  is  usually  a  lacerated  one 
with  sloughs  and  the  infection  is  always  mixed, 
the  aerobic  microbes  producing  the  anaerobic  condi- 
tions necessary  for  the  development  of  the  tetanus 
bacillus  by  absorbing  oxygen  and  distracting  the 
attention  of  the  phagocytes  from  it.  The  toxin 
tetanospasmin  has  a  very  strong  affinity  for  nervous 
tissue  and  is  said  to  reach  the  central  nervous 
system  by  ascending  along  the  nerves  serving  the 
infected  area. 

The    lesions    found  post  mortem  are  confined 
190 


Nervous  System. 


chiefly  to  the  large  gangUonic  cells  of  the  brain  and 
anterior  horns  of  the  spinal  chord  which  show 
evidences  of  degeneration  when  stained. 

Bacteriology. — In  pus  the  bacillus  usually  appears 
as  a  long  slender  rod  3 — 4  /x  in  length  and  0*3 — 0-4  fi 
in  breadth.  It  shows,  in  the  absence  of  oxygen,  slow 
waving  movements;  these  movements  cease  when 
the  bacillus  develops  a  spore,  as  it  does  sometimes  in 
pus  and  always  in  anaerobic  cultures.  The  spores  are 
spherical  and  terminal.  The  non-sporing  bacillus 
has  numerous  lateral  flagella.  The  bacillus  is  Gram- 
positive.  It  grows  well  on  ordinary  broth  or  solid 
media  made  with  freshly  made  extract  of  meat 
which  has  not  been  heated  above  100  deg.  C. 
It  is  strictly  anaerobic  when  grown  in  pure 
culture.  If  other  microbes  are  present,  such  as 
the  Bacillus  subtilis,  it  will  develop  under  aerobic 
conditions. 

The  presence  of  the  tetanus  bacillus  is  generally 
not  recognised  until  the  onset  of  characteristic 
symptoms  infallibly  indicate  its  presence.  If  it  is 
present  in  a  wound  an  injection  of  the  pus  into  a 
rabbit,  guinea-pig  or  mouse  produces  the  charac- 
teristic symptoms. 

It  can  sometimes  be  seen  in  Gram-stained  smears  of 
the  pus,  and  grown  from  this  pus  developing  the 
characteristic  spore  on  culture. 

Prophylaxis, — As  I  have  stated,  once  the  toxin 
becomes  attached  to  the  nerve  cells  it  is  out  of  the 
reach  of  antitoxin  which  acts  by  forming  a  com- 
bination with  the  combining  group  of  the  toxin 
molecule  and  not  by  destroying  its  zymophore 

191 


Therapeutic  Immunisation. 


group  (see  p.  19).  It  is  all-important,  therefore,  to 
give  a  patient  who  has  received  a  gunshot  injury 
or  dirty  wound  a  dose  of  antitoxin  of  at  least 
25  c.c.  at  once  and  to  repeat  the  dose  every  seven 
days  until  there  is  no  probability  of  his  developing 
tetanus,  i.e.,  for  three  or  four  weeks.  This  is  the 
usual  practice.  This  measure  is  usually  effective, 
but  there  is  no  reason  why  a  mixed  immunity  should 
not  be  produced  by  giving  a  small  dose  of  toxin  at 
the  same  time.  Probably  one  dose  of  combined 
toxin  and  antitoxin  would  be  effective.  The  wound 
should  be  treated  with  either  iodine  in  solution  or 
iodoform  in  ether,  since  iodine  destroys  the  zymo- 
phore group  of  the  toxin  molecule. 

Treatment.- — Antitoxin  having  no  effect  on  toxin 
already  attached  to  the  nerve  substance  its  only  use 
in  treatment  is  to  prevent  further  toxin  becoming 
attached,  that  is,  to  neutralise  toxin  in  the  circula- 
tion. Unfortunately,  it  can  neither  get  through  the 
walls  of  the  capillaries  of  the  brain  nor  through  the 
secretory  cells  of  the  choroid  plexus,  so  as  to  gain 
access  to  the  nerve  cells,  so  that  the  only  way  to 
effect  this  is  to  inject  it  into  a  lateral  ventricle  after 
trephining  or  into  the  cerebrospinal  fluid  by  lumbar 
puncture. 

Ballance's  operation  devised  for  the  introduction 
of  salvarsanised  serum  into  the  lateral  ventricle  is 
very  neat.  A  trephine  hole  is  made  in  the  angle 
between  the  sagittal  and  coronal  sutures.  The  dura 
is  incised  and  turned  aside.  The  hemisphere  is 
gently  pulled  sideways  from  the  falx  cerebri  and  a 
small  blunt  trocar  and  cannula  is  pushed  through  the 

192 


Nervous  System. 


anterior  part  of  the  corpus  callosum  into  the  lateral 
ventricle.  Through  the  cannula  the  serum  is 
introduced. 

Generally  about  25  c.c.  should  also  be  given 
intravenously  and  25  c.c.  into  the  tissues  near  the 
wound.  Probably  the  intraventricular  method  is 
the  only  method  of  any  use  in  fulminating  cases. 
Intensive  iodine  therapy  will  probably  prove  very 
useful.  I  think  intravenous  injections  of  i  grain 
(64  mg.)  of  iodoform  in  i  c.c.  of  pure  ether  once  a 
day  or  oftener  or  5  c.c.  doses  of  a  i  per  cent,  solution 
of  sodium  di-iodosalicylate  would  be  well  worth 
trying.  It  is  quite  possible  that  the  iodine,  which 
can  pass  the  barrier  of  the  choroid  plexus,  will 
neutralise  the  toxin  already  attached  to  the  nerve 
cells. 

It  is  absolutely  essential  to  control  the  spasms  by 
reducing  the  sensitiveness  of  the  reflex  mechanism. 
Various  methods  have  been  used,  chloral  or  morphia 
by  the  mouth  ;  10  c.c.  of  a  5  to  25  per  cent, 
solution  of  magnesium  sulphate  intrathecally  or 
subcutaneously  have  been  used  with  success.  I 
have  found  Hutchings'  method  of  giving  60  grains 
(4  grammes)  of  chloretone  in  warm  olive  oil  by 
rectum  daily,  or  as  often  as  necessary,  very 
effective. 

Rabies. — Rabies  or  hydrophobia  is  an  infection 
of  the  central  nervous  system  with  a  virus  intro- 
duced by  bites  of  infected  animals,  such  as  dogs  and 
cats. 

Pathology  and  Bacteriology. — The  organisms  ascend 
to  the  brain  along  the  nerves.  It  is  beheved  that  the 

193  ^3 


Therapeutic  Immunisation. 


bodies  described  by  Negri,  which  vary  in  size  from 
0*5 — 14  /X,  in  the  cells  of  Purkinge  and  the  large 
cells  of  the  cerebral  cortex  and  anterior  horns  of  the 
spinal  cord  are  the  cause  of  the  disease.  More 
recently  Noguchi  has  cultivated  similar  bodies  in 
vitro  and  has  produced  the  disease  with  these 
cultures  in  rabbits,  guinea-pigs  and  dogs.  They 
are  described  as  granular  nucleated  and  corpus- 
cular bodies  and  very  pleomorphic.  The  smallest 
size  must  be  capable  of  passing  through  a 
porcelain  filter,  since  filtered  suspensions  of  the 
brain  of  infected  animals  will  infect.  Leuco- 
cytes accumulate  round  the  blood-vessels  and 
large  motor  nerve  cells  and  also  round  the  cells 
of  the  sympathetic  and  cerebrospinal  ganglia,  in 
fact,  round  all  the  cells  that  harbour  the  Negri 
bodies. 

It  is,  of  course,  of  the  utmost  importance  to  dis- 
cover as  soon  as  possible  whether  or  not  an  animal 
which  has  bitten  the  patient  is  harbouring  the  para- 
site or  not.  The  animal's  brain  should  either  be 
removed  at  once  and  placed  in  10  per  cent,  formalin 
in  normal  saline  or,  better,  the  body  decapi- 
tated, the  head  packed  in  ice  and  despatched  to 
the  laboratory.  If  the  brain  is  allowed  to  decom- 
pose at  all  bodies  produced  by  degeneration  may 
simulate  the  Negri  bodies  which  are  diagnostic. 
Suspensions  of  the  suspected  brain  should  be  in- 
jected under  the  dura  of  rabbits,  which  will  develop 
the  disease  in  fifteen  to  twenty  days  if  the  material 
contains  the  parasite. 

Prophylaxis, — Since  the  disease  is  quite  incurable 
194 


Nervous  System. 


by  present  methods,  once  it  sets  in,  prophylaxis  is 
of  the  first  importance.  Pasteur  found  that  by 
passage  through  about  fifty  rabbits  the  virulence  of 
the  microbe  was  so  increased  that  the  incubation 
period  was  reduced  from  from  fifteen  to  twenty  days 
to  six,  but  could  not  be  reduced  further ;  he  called  this 
the  virus  fixe.  By  keeping  the  spinal  cords  of  rabbits, 
inoculated  intracerebrally  and  dead  from  this  virus, 
in  a  dry  atmosphere  the  virulence  of  an  extract  of 
them  diminished  each  day  until  on  the  fourteenth 
day  it  was  safe  to  inoculate  a  patient ;  by  giving  a 
series  of  inoculations  of  cords  kept  a  shorter  time, 
and  therefore  more  virulent,  the  patient's  immunity 
was  gradually  built  up,  so  that  he  was  able  to  take 
with  impunity  an  inoculation  of  a  cord  of  full 
virulence. 

Emery  gives  a  typical  series  : — 

Day  I. — Inoculation  with  vaccine  made  by  drying 
the  cord  for  fourteen  days.  A  second  injection  with 
a  cord  treated  for  ten  days. 

Day  2. — Two  injections  ;  cords  dried  for  eleven 
and  nine  days. 


Day  3. — One  injection 
Day  4. — One  injection 
Day  5. — One  injection 
Day  6. — One  injection 
Day  7. — One  injection 
Day  8. — One  injection 
Day  9. — One  injection 


cord  dried  for  eight  days, 
cord  dried  for  seven  days, 
cord  dried  for  six  days, 
cord  dried  for  five  days, 
cord  dried  for  four  days, 
cord  dried  for  three  days, 
cord  dried  for  two  days. 


Day  10. — One  injection  ;  cord  of  rabbit  which 
had  died  the  same  day  and  was  therefore  of  full 
virulence. 

195 


Therapeutic  Immunisation. 


In  severe  cases  the  inoculations  are  kept  up  for  a 
longer  period. 

If  Noguchi  has  isolated  the  causative  microbe 
probably  less  laborious  methods  will  be  devised. 

The  incubation  period  in  man  is  generally  two 
months  or  more,  so  that  there  is  usually  plenty  of 
time  to  kill  off  the  microbe  before  it  reaches  the 
central  nervous  system. 

It  has  been  calculated  that  about  15  per  cent,  of 
cases  bitten  by  mad  dogs  and  untreated  develop  the 
disease. 

Thirty  thousand  odd  cases  have  been  treated  at 
the  Pasteur  Institute  with  125  deaths. 

Anterior  Poliomyelitis  is  an  acute  infection  of 
the  central  nervous  system  produced  by  an  organism 
which,  like  that  of  rabies,  is  a  '  filter  passer.' 

Pathology. — The  lesions  are  those  of  an  acute  polio- 
encephalo-myelitis.  The  infection  begins  in  the 
meninges,  to  which  it  spreads  from  the  nose  through 
the  cribriform  plate  of  the  ethmoid  along  the  olfac- 
tory nerves.  Inflammatory  changes  occur  through- 
out the  pia-arachnoid,  consisting  of  perivascular 
small  round-celled  infiltration,  vascular  dilatation, 
oedema  and  small  haemorrhages.  These  changes 
spread  inwards  along  the  pial  septa.  Inflammation 
is  especially  severe  in  the  anterior  cornua,  where 
the  pyramidal  cells  are  especially  affected.  At 
first  the  cerebrospinal  fluid  contains  considerable 
numbers  of  polynuclear  leucocytes,  later  mono- 
nuclear cells  predominate.  This  fluid  is  said  not  to 
be  infective,  in  the  majority  of  cases,  in  animal 
experiment. 

196 


Nervous  System. 


Bacteriology. — In  1913  Flexner  and  Noguchi 
cultivated  and  demonstrated  microscopically  a  small 
filterable  micro-organism  with  which  they  produced 
poliomyelitis  in  monkeys.  They  isolated  from 
throats,  tonsils,  abscesses  in  tonsils  and  from  the 
central  nervous  system  a  peculiar  streptococcus. 
Paralysis  has  been  produced  in  various  animals  by 
intravenous  and  intracerebral  injection  of  cultures 
of  this  organism  and  lesions  of  the  grey  matter  of 
their  central  nervous  system  have  been  demon- 
strated. The  microbe  is  very  pleomorphic  and  its 
size  appears  to  depend  on  the  medium  on  which 
it  is  grown,  even  after  passage  through  a  filter.  It 
is  probable  tha,t  in  the  environment  of  the  central 
nervous  system  the  streptococcus  takes  the  form  of 
the  '  filter  passer. '  This  influence  of  environment  on 
morphology  is  not  peculiar  to  this  microbe,  but  can 
be  demonstrated  on  many  microbes,  even  the  stolid 
Staphylococcus  aureus. 

Prophylaxis  and  Treatment. — So  far  as  T  know  little 
or  no  attempt  has  been  made  to  produce  active  or 
passive  immunity  for  prophylactic  purposes.  One 
attack  of  the  disease,  however  abortive,  protects, 
and  the  serum  of  such  persons  given  intravenously, 
intrathecally,  or  subcutaneously  in  doses  of  5 — 20  c.c. 
has  been  used  with  encouraging  results  in  some 
cases. 

Disseminated  Sclerosis. — One  case  of  this  con- 
dition has  markedly  improved  with  inoculations 
of  a  vaccine  made  from  the  staphylococci  he  was 
excreting  from  his  urine  plus  a  vaccine  (streptococci) 
made  from  his  post-nasal  catarrh  and  B,  coli  vaccine 

197 


Therapeutic  Immunisation. 


from  his  faeces.  Lyon  Smith  and  Grainger  Stewart 
record  a  successful  case  where  the  staphylococcus 
was  isolated  from  the  cerebrospinal  fluid. 

The  Eye. 

The  extraocular  infections  of  the  eye,  that  is, 
infections  of  the  eyelids,  conjunctiva  and  cornea, 
respond  readily  to  specific  therapy.  As  can  be 
easily  imagined  the  intraocular  infections,  unless 
perhaps  recent  wound  infections,  are  much  less  satis- 
factory, since  even  if  the  infection  is  cleared  up  the 
eye  is  often  permanently  damaged.  However,  a  great 
deal  can  be  done  to  help  infections  after  operation. 

Eyelids. — Most  of  the  infections  of  the  eyelids  are 
staphylococcal  in  origin ;  they  are  eczema,  marginal 
blepharitis  and  stye.  Other  infections  associated  with 
special  forms  of  conjunctivitis  can,  of  course,  occur. 

Eczema  of  the  margins  of  the  lids  can  be  caused 
by  other  primary  irritants  than  microbes,  such  as 
irritating  fumes  and  discharges,  but  staphylococci 
generally  invade  the  tissues  whose  resistance  is  thus 
lowered  and  form  part  of  a  vicious  circle.  In  other 
cases  the  staphylococcal  infection  is  primary.  A 
further  stage,  known  clinically  as  marginal  blepha- 
ritis, is  the  infection  of  the  follicles  of  the  eyelashes, 
the  hair  being  surrounded  with  pus,  the  cuticle 
between  the  lashes  is  cast  off  and  crusts  form, 
leaving  a  moist  red  granular  surface  (granulation 
tissue)  when  removed.  The  hair  follicles  may  be 
destroyed  and  the  lashes  cast  off.  In  other  cases  the 
formation  of  fibrous  tissue  distorts  the  follicles  and 
lashes  and  leads  to  lacrimation. 

198 


Eye. 


Styes  are  furuncles,  the  infection  starting  in  the 
glands  of  Moll,  the  hair  follicles  or  the  Meibomian 
glands.  In  the  latter  the  etiology  may  be  similar 
to  that  of  acne,  since  the  primary  infection  may  be 
due  to  the  acne  bacillus  whose  natural  habitat  is  the 
sebaceous  glands. 

Treatment, — The  vaccine  treatment  and  dosage 
of  the  vaccines  is  exactly  similar  to  that  already 
described  for  eczema,  sycosis  and  acne  [q.v.,  p.  i66). 

Conjunctiva  and  Cornea. — Ophthalmia  is  so 
easily  treated  by  local  antiseptic  methods  that  I 
suppose  the  majority  of  eye  surgeons  will  not  think 
any  further  methods  necessary.  However,  no  one 
will  deny  that  in  some  acute  and  chronic  infections 
which  may  lead  to  opacities  in  the  cornea  or  to  its 
perforation  or  even  sloughing  every  weapon  available 
should  be  used. 

Pathology. — There  is  nothing  peculiar  about  the 
pathological  histology  of  the  conjunctiva.  The 
microbial  toxins  may  produce  an  effect  varying  from 
a  slight  hyperaemia  with  a  small  amount  of  sero- 
purulent  discharge  to  sloughing  of  the  conjunctiva 
and  cornea  and  destruction  of  the  eyeball.  Diph- 
theria bacilli,  as  elsewhere,  produce  a  membranous 
slough. 

It  is  not  within  the  scope  of  this  book  to  go  into 
the  pathology  of  the  many  clinical  forms  of  ulcer  of 
the  cornea  ;  the  general  mechanism  of  their  produc- 
tion is  as  follows  :  The  corneal  tissue  is  invaded 
from  the  surface  by  microbes ;  a  collection  of 
leucocytes  occurs  at  the  site  and  the  superficial 
tissues  slough.  When  healing  takes  place  the  trans- 

199 


Therapeutic  Immunisation. 


lucent  corneal  tissues  are  replaced  by  opaque  fibrous 
tissue. 

Bacteriology. — ^Acute  epidemic  catarrhal  oph- 
thalmia is  produced  most  commonly  by  the  Koch- 
Weeks  bacillus,  less  commonly  by  the  Morax- 
Axenfeld  bacillus  or  by  such  microbes  as  the  pneu- 
mococcus.  Very  many  other  microbes  produce 
opththalmia.  The  gonococcus  is  quite  the  most 
important,  for  it  produces  acute  suppurative  in- 
flammation which  frequently  leads  to  permanent 
blindness. 

Pollock  gives  the  following  list  of  microbial 
findings  in  361  cases  : — 

Of  236  cases  of  acute  mucopurulent  catarrh 
177  contained  Koch- Weeks, 
9        ,,  Morax-Axenfeld, 
6  pneumococci, 

2  gonococci, 

I  gonococci  and  Koch- Weeks, 

6  staphylococci, 

4  „       indeterminate  microbes. 
28  were  negative. 

Of  69  cases  of  subacute  catarrh 

7  contained  Koch- Weeks, 

51        ,,  Morax-Axenfeld, 

3  „      undiagnosed  microbes. 

8  were  negative. 

Of  10  cases  of  purulent  catarrh 
3  contained  Koch- Weeks, 
I        ,,       Koch- Weeks  and  B.  subtilis, 
I  pneumococci, 

5  „  gonococci. 

200 


Eye. 


Of  i8  cases  of  ophthalmia 

2  contained  Koch- Weeks  bacilli. 


7 

pneumococci, 

10 

gonococci  (pure), 

I 

„      gonococci  and  streptococci. 

I 

gonococci  and  Koch-Weeks, 

I 

gonococci  and  pneumococci, 

I  was 

negative. 

Two  cases  of  membranous  conjunctivitis  con- 
tained staphylococci. 

Sixteen  cases  of  phlyctenular  conjunctivitis  were 
negative. 

Of  10  cases  of  catarrh  complicated  with  ble- 
pharitis 

2  contained  Morax-Axenfeld  bacilli, 
5  staphylococci, 
2  staphylococci  and  streptococci. 

I  was  negative. 
So  that  apart  from  the  specific  microbes  the 
Koch- Weeks  and  Morax-Axenfeld  bacilli  the  most 
common  enemies  are  the  gonococcus,  pneumococcus, 
staphylococcus  and  streptococcus. 

A  diphtheroid  bacillus,  the  B.  xerosis,  is  a  common 
inhabitant  of  the  conjunctival  sac,  as  is  also  the 
Staphylococcus  epidermidis. 

Treatment. — The  infections  with  the  Koch- Weeks 
and  Morax-Axenfeld  bacilli  appear  to  be  so  amenable 
to  antiseptic  treatment  that  no  special  means  need 
be  employed  in  their  treatment. 

In  acute  suppurative  inflammation  serum,  if 
available,  or  vaccine  should  be  used  at  once.  The 
only  sera  likely  to  be  effective  are  anti-pneumonic  or 

201 


Therapeutic  Immunisation. 


anti-streptococcic,  and  they  can  be  given  both  sub- 
cutaneously  and  also  instilled  into  the  conjunctival 
sac.  Pending  the  making  of  an  autogenous  vaccine 
stock  vaccine,  if  available,  should  be  used.  The 
commercial  gonococcic  and  pneumococcic  vaccines 
are  of  very  weak  toxicity  and  comparatively  large 
doses  can  be  used  ;  lo  million  of  either  may  be  given 
as  an  initial  dose  to  an  infant  and  50  million  to  an 
adult.  If  these  vaccines  are  made  from  the  patient 
or  from  a  recently  isolated  microbe  i  million  is 
quite  a  large  enough  initial  dose  for  an  infant  and 
2 J  million  for  an  adult,  and  the  progression  is 
5.  7h  io>  ^5>  20,  30,  50,  75,  100,  150,  200 
million. 

Commercial  streptococcus  vaccine  is  more  effi- 
cient and  the  smaller  doses  mentioned  should  be 
used. 

The  doses  of  staphylococcus  vaccine  may  be 
50  million  in  children  and  acute  cases,  100  million 
in  adults  and  chronic  cases. 

In  chronic  cases  very  large  doses  may  have  to  be 
reached  before  complete  success  is  attained.  In 
one  case  of  trachoma  with  pannus  and  a  secondary 
infection  with  the  Staphylococcus  aureus  a  dose  of 
10,000  million  of  a  vaccine  of  this  microbe  was 
reached.  This  case  had  resisted  all  local  treatment 
and  the  man  was  unable  to  read  anything  but  large 
print,  and  that  only  with  one  eye.  The  condition 
cleared  up  in  a  most  satisfactory  manner,  leaving 
nearly  perfect  vision  in  one  eye  and  only  a  slight 
opacity  in  the  other. 

Intraocular  Infections  occur  from  wounds, 
202 


Eye. 


either  perforation  of  a  corneal  ulcer,  operation  in- 
cisions or  accident,  or  through  the  blood-stream. 

Bacteriology. — According  to  Axenfeld  the  pneu- 
mococcus  is  the  most  frequent  operation  wound 
infection,  but  any  of  the  pathogenic  microbes  may 
be  the  cause,  especially  those  infecting  the  nose 
and  'mouth  and,  not  uncommonly,  the  saprophytic 
B.  xerosis  and  the  Staphylococcus  epidermidis  become 
pathogenic. 

In  infections  produced  by  accident  other,  usually 
saprophytic,  microbes,  such  as  the  B,  subtilis,  when 
introduced  into  the  vitreous  become  pathogenic.  In 
such  cases  the  only  thing  to  do  is  to  remove  the  eye. 

In  blood-borne  infections  a  focus  of  infection  will 
always  be  found  elsewhere.  Iridocyclitis  is  most 
common  in  rheumatic  conditions  and  the  commonest 
cause,  therefore,  streptococci.  I  have  treated  a  case 
of  chronic  iridocyclitis  with  a  vaccine  made  from  a 
diphtheroid  bacillus  isolated  in  pure  culture  from 
a  chronic  nasopharyngitis  ;  marked  focal  reactions 
occurred  so  that  there  can  be  no  doubt  that  this  was 
the  infecting  microbe.  Quite  as  commonly,  the 
infecting  microbe  can  be  isolated  from  pyorrhoea 
alveolaris. 

Treatment. — In  infected  operation  wounds  the 
microbe  can  be  isolated  from  them.  Although  I 
have  no  personal  experience,  I  have  no  doubt 
vaccines,  if  given  according  to  the  principles  already 
laid  down  in  this  book,  will  be  of  very  great  help  in 
these  very  anxious  cases.  The  treatment  of  rheu- 
matic infections  need  not  be  repeated  ;  they  have 
already  been  treated  of  (see  p.  156). 

203 


Therapeutic  Immunisation. 


The  Ear. 

From  the  point  of  view  of  local  therapy  the 
infections  of  the  Eustachian  tube  and  middle  ear 
are  very  unsatisfactory  owing  to  their  inaccessible- 
ness  ;  this  is  especially  so  when  the  mastoid  cells 
and  labyrinth  become  involved,  when  recourse  must 
be  had  to  operation  if  involvement  of  the  meninges 
or  lateral  sinus  is  to  be  prevented. 

Pathology. — The  infection  is  practically  always  a 
sequel  to  that  of  the  nasopharynx. 

The  Eustachian  tube  is  first  involved,  its  mucous 
membrane  becoming  swollen  owing  to  serocellular 
infiltration  of  its  tissues  with,  at  first,  a  serous  dis- 
charge on  the  surface  which  becomes  mucopurulent. 
It  soon  becomes  obstructed,  the  closure  taking  place 
first  at  its  narrowest  part,  the  isthmus.  The  inflam- 
mation may  then  spread  to  the  tympanum,  the 
surface  spread  being  probably  helped  by  the  closure 
of  the  tube,  absorption  of  the  air  producing  a  negative 
pressure  tending  to  the  aspiration  of  infected  dis- 
charge into  the  cavity  and  to  retraction  of  the  drum. 
According  to  the  kind  of  microbe  or  the  quality  of 
its  toxins  the  inflammation  may  be  catarrhal  or 
suppurative. 

The  changes  in  the  lining  membrane  of  the 
tympanum  are  similar  to  those  in  the  Eustachian 
tube,  the  muco-sero-cellular  secretion  poured  out 
on  the  surface  fills  up  the  cavity,  the  cells  of  the 
mastoid  and  the  pockets  of  mucous  membrane  in  the 
attic.  The  membrana  tympani  is  involved  and  the 
inflammatory  changes  spread  along  the  walls  of  the 

204 


Ear. 


external  auditory  meatus,  where  often  bullae  are 
formed.  If  the  microbial  toxins  are  pyogenic  the 
effusion  rapidly  becomes  purulent.  As  a  rule  per- 
foration and  discharge  takes  place  through  the  mem- 
brana  fiaccida.  In  the  worst  cases  the  drum  becomes 
totally  destroyed  and  necrosis  of  the  ossicles  takes 
place  and  acute  osteitis  and  necrosis  of  the  mastoid. 
Involvement  of  the  tegmen  tympani  leads  to  abscess 
in  the  brain  ;  and  of  the  wall  of  the  lateral  sinus 
to  septic  thrombosis  and  pyaemia. 

Non-suppurative  inflammation  may  be  so  subacute 
from  the  start  as  to  attract  little  attention  until 
gradually  increasing  deafness  is  noticed. 

Bacteriology. — The  infection  is  very  commonly  a 
mixed  one.  By  far  the  most  common  primary  infec- 
tion is  the  streptococcus ;  this  is  not  surprising,  as  it 
is  the  most  common  cause  of  post-nasal  catarrh.  In 
scarlet  fever  the  condition  may  be  caused  by  the 
diplo-streptococcus,  the  probable  cause  of  that 
disease,  or  by  the  ordinary  Streptococcus  brevis  or 
both.  A  combination  of  staphylococcus  and  strepto- 
coccus is  common,  as  is  also  the  pneumococcus  and 
pneumobacillus.  Other  Gram-negative  bacilli  of 
various  kinds  are  not  uncommon,  e.g.,  the  ozoena 
bacillus  and  the  B.  pyocyaneus.  Various  Gram- 
positive  and  diphtheroid  bacilli  are  not  infrequently 
found  and  microbes  of  the  Micrococcus  catarrhalis 
group.  Except  during  epidemics  of  them  the 
influenza  and  whooping-cough  bacilli  are  uncommon. 
The  causative  microbes  can  be  obtained  from  the 
discharge  via  the  perforation  if  it  is  present  or  by 
incision  if  bulging  of  the  membrane  shows  that  pus  is 

205 


Therapeutic  Immunisation. 


present.  In  chronic  cases  the  microbes  isolated  from 
the  discharge  in  the  nasopharynx  may  be  assumed 
to  be  the  cause  of  the  changes  in  the  tympanum. 

Furunculosis  in  the  external  meatus  is  nearly 
always  staphylococcal,  and  eczema  of  it,  if  secondary 
to  middle  ear  disease,  is  caused  by  the  microbes 
producing  this,  plus  staphylococci  as  a  complicating 
infection. 

Prophylaxis  and  Treatment. — Middle  ear  disease, 
following  as  it  does  on  acute  and  chronic  post-nasal 
infection,  is  an  additional  and  potent  reason  for  not 
allowing  post-nasal  catarrh  to  continue.  As  I  have 
already  said,  a  few  injections  of  vaccine  of  the 
causative  microbes  in  the  acute  stages  will  usually 
insure  this.  In  such  diseases  as  scarlet  fever  specific 
therapy  with  streptococcal  serum  or  vaccine  or 
both  will  prevent  these  complications. 

If  middle  ear  suppuration  occurs  the  discharge 
should  be  liberated  at  once  by  incision  and  a  vaccine 
prepared.  It  is  remarkable  how  rapidly,  in  the 
acute  stages,  suppuration  in  the  middle  ear  can  be 
controlled,  provided  the  vaccine  contains  all  the 
causative  microbes.  The  dosage  is  the  same  as  for 
post-nasal  catarrh  and  has  already  been  described 
(see  pp.  113,  114). 


206 


CHAPTER  XII. 


INFECTIONS  PRODUCED  BY  STREPTOTHRICES. 

Tubercular  Infections. — The  tubercular  infec- 
tions of  the  different  tissues  are  being  considered 
together,  since  the  essential  changes  and  treatment 
are  similar.  Tubercular  disease  of  the  lungs  is  too 
big  and  important  a  subject  for  a  single  chapter  and 
has  been  dealt  with  in  a  separate  book.^ 

Pathology. — The  effect  of  streptothrices  on  the 
tissues  is  to  produce  granulomata,  the  cells  of  the 
tissue  being  destroyed  and  replaced  by  masses  of 
cells  newly  formed  under  the  stimulus  of  the  microbe. 
The  miliary  tubercle  is  the  primary  formation.  It 
consists  of  a  central  mass  of  epithelioid  cells  pro- 
duced by  the  division  of  the  endothelial  cells  of  the 
part  and  also,  in  the  lungs,  by  division  of  the 
alveolar  epithelium.  The  central  mass  of  cells 
becomes  surrounded  by  small  round  cells  produced 
by  reaction  of  the  tissues.  If  the  condition  is  very 
acute  and  generalised  the  lesion  does  not  get  beyond 
this  stage  owing  to  the  death  of  the  patient,  the 
tubercle  being  about  the  size  of  a  millet  seed.  If 
the  disease  is  more  chronic,  giant  cells  form ;  they 
arise  by  the  nucleus  of  an  epithelioid  cell,  which 
has  ingested  tubercle  bacilli,  dividing  and  sub- 
dividing without  division  of  the  protoplasm.  As 
the  mass  gets  larger  the  toxins  of  the  microbe  and 

1    Pulmonary  Tuberculosis."    J.  &  A-  Churchill. 
207 


Therapeutic  Immunisation. 


the  cutting  off  of  nutrition  produce  necrosis  of  a 
peculiar  kind,  the  cells  losing  their  identity  and  being 
converted  into  a  uniform  cheesy  mass.  This  casea- 
tion spreads  outwards  with  the  invasion  of  the 
tissues  by  the  infection,  so  that  by  this  invasion  and 
the  coalescence  of  neighbouring  areas,  large  masses 
of  caseous  material  may  form.  In  hard  tissues  such 
as  bone,  masses  of  the  bone  may  die  undestroyed  by 
the  tubercle  bacillus,  but  killed  by  the  cutting  off 
its  blood  supply.   In  this  way  sequestra  form. 

If  the  patient's  immunising  mechanism  responds 
sufficiently  the  disease  is  got  rid  of,  either  by  its 
isolation  due  to  the  reaction  of  the  tissues  producing 
dense  masses  of  fibrous  tissue  which  gradually 
contracts,  while  lime  salts  may  be  laid  down  in  the 
caseous  mass,  or,  more  commonly,  the  caseous  mass 
softens  down  into  tubercular  pus,  a  thick  creamy 
fluid  characterised  by  the  absence  of  polynuclear 
pus  cells,  which  burrows  its  way  along  a  path  of 
least  resistance  to  the  surface  by  a  process  of  pressure 
and  colliquative  necrosis.  A  sinus  is  thus  formed, 
which  commonly  becomes  invaded  by  pyogenic 
microbes.  This  is  always  the  case  when  the  disease 
is  superficial  and  the  necrosis  produces  ulceration  as 
in  lupus  and  in  the  intestine,  where  the  process 
starts  in  the  Peyer's  patches.  A  mixed  infection  is 
the  rule  rather  than  the  exception  in  the  lungs 
and  also  in  tubercular  glands  in  the  neck,  where  the 
tonsils  are  the  source  of  infection,  as  a  rule.  In  the 
case  of  bones,  if  the  infection  is  overcome  by  suitable 
treatment,  for  instance,  in  cancellous  tissue,  the 
diseased  bone  may  be  absorbed  and  new  bone  laid 

208 


Infections  Produced  by  Streptothrices. 


down  so  that  the  bone  is  reconstituted.  If  a  large 
mass  of  bone  is  destroyed,  for  instance,  the  whole  of 
the  shaft  of  a  long  bone,  it  can  be  removed  and,  if 
the  periosteum  is  intact  and  a  suitable  skeleton 
provided,  a  new  functionally  perfect  bone  is  pro- 
duced. The  cellular  changes  described  have  as  their 
object  the  isolation  of  the  infected  area  by  reaction 
of  the  tissues  and  the  ingestion  and  digestion  of  the 
microbe  by  the  epithelioid  cells.  The  microbe  pro- 
duces no  chemiotactic  substance  for  the  polynuclear 
leucocytes,  which  do  not  arrive  on  the  scene  unless 
other  microbes  are  present,  when  they  also  ingest 
tubercle  bacilli.  The  efficiency  of  the  phagocytosis  is 
dependent  on  the  formation  of  immune-body  and 
antitoxins  by  the  tissues  in  general. 

Bacteriology. — ^The  tubercle  bacilli  as  they  occur 
in  the  tissues  are  2-5  /x  in  length  and  about  0-3  /x  in 
thickness.  They  are  straight  or  slightly  curved  and 
often  exhibit  unstained  areas — polar  staining.  They 
are,  as  a  rule,  acid-fast,  not  being  decolorised  by 
acid  when  stained  with  carbol  fuchsin,  but  some- 
times, especially  when  young,  they  are  not  acid-fast, 
but  can  be  demonstrated  by  a  modification  of  Gram's 
method.  The  bacillus  can  split  up  in  the  tissues 
into  minute  granules,  acid-fast  or  non-acid-fast, 
which  are  infective.  By  injecting  tubercle  bacilli 
into  a  solid  organ  like  the  kidney,  or  under  the  dura 
mater  of  an  animal,  spherical  masses  may  form, 
consisting  of  radiating  filaments  with  clubbed  ends. 

There  are  several  strains  of  tubercle  bacilli,  viz., 
the  human,  bovine,  and  avian  types.  In  lupus, 
which  can  be  produced  by  either  the  human  or 

T.I.  209  ^4 


Therapeutic  Immunisation. 


bovine  type,  the  infection  is  of  low  virulence.  A 
large  proportion  of  the  cases  of  tuberculosis  in 
children  are  caused  by  the  bovine  type,  the  infection 
being  conveyed  in  milk.  Most  cases  of  pulmonary 
tuberculosis  and  of  '  surgical '  tuberculosis  in  adults 
are  produced  by  the  human  type.  Both  types  are 
equally  infective  to  man. 

Methods  of  Invasion. — There  are  two  vehicles  for 
tubercle  bacilli — uncooked  food  and  air.  Milk  and 
butter  are  the  principal  food  vehicles  of  the  bovine 
type.  Since  the  human  type  bacillus  does  not  cause 
disease  in  the  cow  all  cases  produced  by  milk  are 
bovine  in  origin.  The  infection  is  conveyed  by  the 
air  in  the  form  of  atomised  sputum  or  dust.  What- 
ever the  method  of  infection,  the  bacilli  are  conveyed 
by  leucocytes  through  the  mucous  membrane, 
especially  at  sites  of  collections  of  lymphoid  cells, 
such  as  the  tonsils,  Peyer's  patches,  lymphoid  areas 
in  the  bronchi  and  through  the  stomata  of  the  pulmo- 
nary alveoli,  into  the  lymphatic  system.  They  may 
be  destroyed  at  once  or  be  isolated  in  the  lymph 
glands,  where  they  set  up  a  chronic  infection,  or  the 
infection  in  these  glands  may  act  as  a  source  of  slow 
general  infection  of  the  blood  stream.  Blocking  of 
glands  may  produce  a  reversal  of  the  lymph  stream 
of  a  particular  area,  and  the  infection  may  spread 
peripherally,  producing  disease,  for  instance,  in  the 
lungs  and  pleura  in  the  case  of  the  glands  of  the 
hilus,  in  the  peritoneum  or  intestine  in  the  case  of 
the  abdominal  glands.  If  the  infection  is  severe  the 
lymphoid  entrance  gate  becomes  markedly  infected 
and  ulcerates,  the  ulceration  being  increased  by 

210 


Infections  Produced  by  Streptothrices. 


invasion  with  other  microbes,  especially  the  B.  coli 
in  the  intestine. 

If  a  broken-down  gland  ulcerates  into  a  vein  acute 
miliary  tuberculosis  results.  Evidently  an  infection 
may  lurk  for  years  in  the  lymphatic  gland  traps,  in 
patients  whose  immunity  is  not  just  sufficient  to  kill 
them  off  entirely,  until  invasion  by  other  microbes 
or  other  cause  of  lowering  resistance,  e.g,,  psycho- 
logical, alcoholic  or  environmental,  determines  its 
spread. 

The  tubercle  bacillus  can  be  grown  in  pure  culture 
by  two  methods.  The  tissue  or  discharge  containing 
it  can  be  treated  with  antiformin  (equal  parts  of 
liq.  sodae  chlorinatae  B.P.  and  15  per  cent,  caustic 
soda),  which  destroys  rapidly  all  other  microbes 
(except  spores)  but  the  tubercle  bacillus  and 
liquefies  the  material,  which,  after  this  treatment  for 
varying  times  up  to  half  an  hour,  is  centrifuged  and 
cultures  made  from  the  deposit.  Or  the  infected 
material  can  be  broken  up  in  water  and  injected 
into  a  rabbit  or  guinea-pig,  which  does  the  killing 
off  of  the  other  microbes.  An  infected  gland  is 
then  removed  aseptically,  broken  up  and  inoculated 
on  egg  slopes  or  other  suitable  media. 

The  tubercle  bacillus  does  not  grow  well  on 
ordinary  -f  10  agar,  but  it  does  much  better  if 
fresh  human  blood  is  added.  Both  human  and 
bovine  bacilli  grow  excellently  on  Dorset's  egg 
medium,  the  addition  of  glycerine  to  which  is  said 
to  increase  the  growth  of  the  human  type  and 
inhibit  the  growth  of  the  bovine  type.  Both  types 
grow  quite  well  on  plain  egg  medium.  If  the  medium 

211  '4-^ 


Therapeutic  Immunisation. 


is  to  be  used  for  making  tuberculin,  fresh  human 
blood  should  be  added.  The  microbe  grows  well  on 
serum  media  and  glycerine  veal  broth.  Further 
details  are  outside  the  scope  of  this  book. 

Prophylaxis. — The  tubercle  bacillus  is  so  universally 
present  that  it  is  practically  impossible  to  prevent 
infection,  as  the  accompanying  table  shows. 


Incidence  of  Tuberculosis  in  Vienna. 


Diagnosed  by : — 

Autopsy. 

Tuberculin  Reactions. 

Lethal; 
Non- 
lethal. 

Non- 
lethal 
only. 

Cutaneous. 

Cutaneous 
and  In- 
jectional. 

Investigator : — 

Ghon. 

Ghon. 

V.  Pirquet. 

Gang- 
hofner. 

Hamburger 
and  Monti. 

Hamburger 
and  Monti. 

2nd  year  of  life 
3rd — 4th  years 
5th-^6th 
yth — loth 
nth — 14th 

Per 
cent. 
40 
60 
56 
63 
70 

Per 
cent. 

17 

30 
34 
35 
53 

Per 
cent. 
2 
13 
17 

35 
55 

Per 
cent. 
12 
27 

47 
57 
70 

Per 
cent. 

9 
23 
36 
47 
51 

Per 
cent. 

9 
27 
51 
71 
94 

The  large  majority  of  cases  that  get  infected 
overcome  the  disease,  their  immunising  mechanism 
being  normal.  Those  whose  resistance  is  subnormal, 
however,  develop  the  disease.  The  lowering  of  their 
resistance  may  be  due  to — 

1.  Bad  hygienic  surroundings. 

2.  Infection  with  other  microbes.  , 

3.  Inheritance  of  a  low  resistance. 

4.  The  overcoming  of  a  normal  resistance  by  a 

virulent  or  continuous  infection. 
I.  The  effect  of  bad  environment  is  well  illustrated 
212 


Infections  Produced  by  Streptothrices. 


by  figures  of  tuberculosis  mortality  among  the 
different  classes  in  the  Dublin  registration  area  for 

Professional  and  independent  classes  1-84  per  1,000 
Middle  class         .        .        .  .2-18 
Artisans  and  shop  keepers     .        •  3'ii 
General  service  classes  .        .        .  3-61 

It  is  often  argued  that  improvement  of  hygienic 
surroundings — good  housing,  food,  etc. — is  all  that 
is  necessary  to  stamp  out  the  disease.  That  a  good 
environment  is  essential  is  obvious  from  these 
figures.  And  yet,  since  we  may  take  it  that  the 
middle  class  enjoy  a  sufficiently  good  environment, 
and  usually  die  at  home,  while  their  death-rate  from 
the  disease  is  1-92  per  1,000,  it  is  clear  that  something 
else  is  necessary. 

2.  Infections  with  other  microbes  often  lower 
resistance — measles,  whooping-cough,  and  so  on. 
In  the  alimentary  canal  when  sputum  is  swallowed 
containing  a  mixture  of  tubercle  bacilli  and  virulent 
catarrh  microbes,  these  latter  are  potent  factors  in 
lowering  the  resistance  of  the  intestine  to  the 
tubercle  bacillus. 

3.  Inherited  Low  Resistance.  As  I  have  written 
elsewhere  (''Pulmonary  Tuberculosis"),  it  seems  to 
me  unreasonable  to  suppose  that  germ  cells  inhabiting 
a  person  poisoned  with  tubercular  toxin  should  not 
participate  in  the  poisoning  effect  and  hand  on  the 
lowered  resistance,  especially  if  the  infected  person 
is  the  mother.  Karl  Pearson  has  investigaged  the 
matter  statistically,  and  has  come  to  the  conclusion 
that  this  supposition  is  true. 

213 


Therapeutic  Immunisation. 


4.  A  normal  resistance  may  be  overcome  by  a 
massive  or  continuous  infection  with  virulent 
microbes. 

The  most  common  source  of  this  infection  in 
infants  and  children  is  infected  milk.  A  large  pro- 
portion of  milch  cows  supplying  milk  to  cities  have 
been  found  to  be  infected,  as  many  as  nine  out  of 
thirty-five  in  one  case,  and  these  without  obvious 
disease  of  their  udders.  A  properly  managed 
municipal  milk  supply  from  immunised  cows  is  the 
only  sound  solution  of  the  milk  difficulty ;  in  no  other 
way  can  rich  or  poor  be  assured  of  a  sound  supply  at 
a  reasonable  figure. 

There  is  only  one  certain  method  of  bringing  up  a 
low  resistance  to  a  microbe  to  normal  or  of  increasing 
a  normal  resistance,  and  that  is  the  production  of 
specific  antibodies  or  of  a  mechanism  facile  in  the 
production  of  these  antibodies  in  the  individual  by 
inoculating  him  with  the  toxin  or  vaccine  of  that 
microbe.  In  the  case  of  a  universal  infection  like 
tuberculosis  it  is  the  one  measure  that  will  protect 
when  the  constitutional  resistance  is  lowered  by 
the  various  environmental  and  inherited  causes  of 
low  resistance.  I  give  the  following  series  of  doses 
of  a  solution  of  the  tubercle  bacillus,  human  or  bovine 
type,  H.T.S.  orB.T.S.  (see  p.  217),  in  benzoyl  chloride, 
to  an  infant  of  three  months  or  more  at  weekly 
intervals  :  -oooooi  mg.,  -ooooi  mg.,  -oooi  mg., 
•001  mg.  For  older  children,  unless  they  are  sus- 
pected of  being  tubercular,  when  the  first  dose 
should  be  -ooooooi  mg.,  the  series  may  be  -oooooi 
mg.,  -OOOOI  mg.,  -0001  mg.,  -ooi  mg.,  and  'Oi  mg. 

214 


Infections  Produced  by  Streptothrices. 


For  adults  an  additional  dose  of  O'l  mg.  may  be 
added. 

Diagnosis. — There  is  an  additional  advantage  in 
doing  this  preventive  inoculation,  for  if  the  patient 
is  tubercular  a  reaction  will  occur  after  one  of  the 
doses,  and  a  proper  course  of  treatment  can  be 
instituted  while  the  disease  is  easily  curable.  In 
this  way  tuberculosis  of  bones,  joints,  kidneys  and 
other  organs  can  be  discovered  in  its  early  stages,  by 
the  occurrence  of  focal  reactions,  and  recovery  thus 
assured  with  the  minimum  of  damage. 

The  doses  should  be  -ooooooi  mg.,  -oooooi  mg., 
•poooi  mg.,  -0001  mg.  H.T.S.  or  B.T.S.  If  no 
reaction  occurs  after  any  of  them  the  lesion  is  most 
unlikely  to  be  tubercular.  It  must  not  be  forgotten 
that  the  relief  of  focal  symptoms  is  just  as  significant 
as  their  increase  for  diagnostic  purposes.  If  tubercle 
solution  is  not  available  A.T.  (old  tuberculin)  may 
be  used;  the  doses  should  be  o-i  c.mm.,  o-2  c.mm., 
0*4  c.mm.  and  i  c.mm.  The  intervals  between  the 
doses  should  be  forty-eight  hours,  as  sometimes  the 
reaction  does  not  come  on  for  twenty-four  to  thirty- 
six  hours.  The  inoculations  should  be  given  sub- 
cutaneously,  care  being  taken  that  the  needle  is 
not  in  a  vein  before  injecting,  and  that  it  is  not 
given  into  an  area,  the  lymphatics  of  which  drain 
into  glands  which  may  possibly  be  infected,  that  is, 
they  should  be  given  into  an  area  as  far  from  the 
lesion  as  possible. 

Treatment. — The  treatment  of  chronic  tuber- 
culosis of  the  lungr,  except  before  the  '  open  '  stage, 
by  tuberculin  alone  has  been  a  failure  because  the 

215 


Therapeutic  Immunisation. 


infection  is  nearly  always  a  mixed  one.  A  similar 
failure  may  be  expected  in  tuberculosis  of  other 
tissues  under  similar  conditions.  If  a  tubercular 
abscess  has  burst  on  the  surface  and  the  sinus 
becomes  infected  the  secondary  infection  must  be 
cleared  up  first  before  starting  tuberculin.  Some- 
times, but  not  often,  the  tubercular  infection  is 
secondary  to  chronic  infections  with  other  microbes, 
such  as  the  diplostreptococci,  the  common  primary 
cause  of  rheumatism. 

Any  pyogenic  microbe  may  be  the  secondary 
invader,  the  most  common  being  staphylococci, 
streptococci  or  B.  coli.  As  usual  the  initial  dose  of 
staphylococci  may  be  25  to  100,  according  to  the  age 
and  condition  of  the  patient,  and  the  series  25,  50, 
100,  200,  400,  600,  800,  1,000  million,  and  higher  if 
necessary ;  that  of  the  other  microbes  2 J  million,  and 
the  series  2^,  5,  7|,  10,  15,  20  million,  and  so  on. 
Especial  care  should  be  taken  if  the  secondary  infec- 
tion is  B.  pyocyaneus,  a  safe  series,  such  as  i,  2,  4, 
6,  8,  10,  etc.,  being  necessary,  as  this  microbe  is 
frequently  exceedingly  poisonous. 

If  the  tubercle  infection  is  closed,  or  if  there  is  no 
evidence  of  secondary  infection  of  the  sinus,  treat- 
ment with  tubercle  bacillus  antigen  may  be  begun  at 
once.  These  tubercle  bacillus  antigens  or  tuber- 
culins are  of  many  kinds  and  of  varying  degrees  of 
efficiency.  Of  all  the  usually  used  tuberculins 
Koch's  old  tuberculin  (A.T.),  which  is  a  concen- 
trated filtrate  of  a  glycerine-veal-broth  culture,  is 
as  good  as  any.  There  are  many  others  produced  by 
Koch,  such  as  A.F.  or  albumose-free  tuberculin, 

216 


Infections  Produced  by  Streptothrices. 


T.R.,  an  extract  of  the  ground-up  bacilli,  T.O., 
a  by-product  of  the  manufacture  of  T.R.  and  B.E. 
or  bacillary  suspension.  Corresponding  preparations 
of  the  bovine  type  are  also  used,  called  P.A.T., 
P.T.R.,  P.T.O.,  P.B.E.  One  often  finds  that  when 
the  human  type  gives  too  much  reaction  the  bovine 
type  will  not,  and  vice  versa.  The  initial  doses  of 
A.T.,  A.F.  and  P.T.O.  are  the  same,  varying, 
according  to  the  age  and  condition  of  the  case,  from 
•001  c.mm.  to  -oi  c.mm.  The  initial  dose  of  T.R. 
should  not  be  larger  than  -oooi.  Although  it  is  not 
a  mathematical  progression  I  find  the  series  i,  2,  4, 
6,  8,  10,  e.g.,  -01,  -02,  -04,  -06,  -08,  -I,  answers  all 
practical  purposes  and  is  safe.  If  the  patient  is 
not  having  marked  reactions  one  can  shorten  the 
course  by  omitting  the  6's  and  often  the  I's,  skip- 
ping, for  instance,  from  -04  to  -08  and  from  this 
to  -2  in  the  above  example.  However,  it  generally 
pays  to  go  slowly  and  not  to  risk  undue  reactions. 

I  have  never  found  it  necessary  to  attain  doses 
higher  than  10  c.mm.  of  any  of  the  above  prepara- 
tions. 

The  intervals  between  the  doses  depend  entirely 
on  reactions.  If  there  is  no  apparent  reaction, 
focal  or  general,  the  next  dose  may  be  given  in  forty- 
eight  hours,  that  is,  with  one  clear  day's  interval. 
If  there  is  a  reaction  three  clear  days  should  be  left 
after  all  signs  of  it  have  disappeared  and  then  the 
next  dose  given,  or  if  it  has  been  severe  the  last  dose 
repeated.  If  the  patient  gets  continuous  unpleasant 
reactions  with  one  type  of  tuberculin  it  is  well  to 
change  to  the  other. 

217 


Therapeutic  Immunisation. 

None  of  these  tuberculins  are,  in  my  experience, 
as  good  antigens  as  the  benzoyl  chloride  solutions, 
which  I  have  already  mentioned.  These  appear  to 
me  to  be  more  likely  to  have  all  the  essential  anti- 
genic substances  present,  since  they  are  solutions  of 
living  tubercle  bacilli,  the  waxy  constituent  of  which 
is  soluble  in  benzoyl  chloride,  but  not  in  water.  It 
might  be  thought  that  the  endotoxin  would  be 
destroyed  by  the  solvent,  but  the  success  of  the 
product  clinically  would  point  to  this  not  being  the 
case.  The  initial  dose  of  these  is  'ooooooi  mg. 
or  'Oooooi  mg.,  according  to  the  age  and  condi- 
tion of  the  patient,  and  the  progression  -000002, 
•000004,  -000006,  -000008,  -ooooi,  and  so  on,  up  to 
•01  mg.,  or  occasionally  o-i  mg.  The  dilutions  are 
made  in  liquid  paraffin  containing  2  per  cent,  of 
benzoyl  chloride.  As  in  the  case  of  the  other 
tuberculins,  it  is  often  possible  to  skip  the  6's  and 
sometimes  the  I's. 

The  directions  for  intervals  between  doses  are  the 
same  as  for  the  other  tuberculins. 

A  combination  of  iodine  therapy  and  immuno- 
therapy, as  in  other  cases,  gives  the  best  results. 
Either  iodoform  intravenously  in  ether  or  the 
iodine-menthol-radium  compound  act  well.  An 
excellent  way  of  exhibiting  iodine  therapy  in 
children,  especially  in  tubercular  peritonitis,  is  to 
rub  an  amount  of  ung.  iodoformi  B.P.,  the  size  of  a 
pea,  daily,  into  the  skin  of  the  abdomen.  Of  course 
every  adjuvant  measure  should  also  be  used, 
e.g.,  abscesses  drained,  sequestra  removed,  joints 
immobilised,  and  so  on. 

218 


Infections  Produced  by  Streptothrices. 


Actinomycosis. — The  ray  fungus  also  produces 
a  granuloma. 

Pathology, — The  most  common  primary  site  of 
infection  is  the  jaw,  where  a  subperiosteal  collection 
of  cells  forms,  which  may  be  mistaken  for  a  sarcoma 
until  suppuration  occurs.  These  epithelioid  cells 
may  fuse  to  form  giant  cells  and  are  phagocytic. 
In  the  pus  the  little  yellow  masses,  0-5 — 2  mm.  in 
size,  of  the  fungus  are  seen.  Any  organ  of  the  body 
may  become  infected,  especially  the  lungs,  in  which 
the  physical  signs  and  symptoms  resemble  those  of 
tuberculosis.  The  lesions  nearly  always  become 
secondarily  infected. 

Bacteriology, — There  are  several  species  of  actino- 
myces  which  infect  man,  the  most  common  is  the 
Actinomyces  {Discomyces)  bovis.  The  above-men- 
tioned masses  consist  of  a  central  mass  of  segmented 
filaments  (mycelium),  the  terminal  radiating  seg- 
ments of  which  are  club-shaped.  The  filaments 
measure  about  10 — 12  fi  long  and  the  clubs  20 — 30  fi 
long  by  8 — 10  broad.  The  filaments  are  Gram- 
positive  and  acid-fast,  but  more  easily  decolorised 
than  the  tubercle  bacillus.  The  clubs  are  decolorised 
in  both  methods. 

The  organism  is  best  isolated  by  sowing  the 
yellow  granules  on  gelatine  plates  after  thorough 
washing  in  sterile  waten  The  granules  that  do  not 
become  surrounded  by  a  halo  of  other  microbes  are 
then  picked  off  and  sewn  on  serum  or  glycerine-agar 
slopes.  The  colonies  are  yellowish-white,  dry,  firm 
and  wrinkled,  and  soon  become  confluent. 

Treatment, — Vaccine  therapy  has  proved  to  be  by 
219 


Therapeutic  Immunisation. 


far  the  most  successful  method  of  treatment.  It 
may  be  usefully  combined  with  iodine  therapy. 
The  vaccine  is  made  by  breaking  up  the  masses 
picked  out  of  the  pus  and  washed,  or  the  growth  on 
the  culture,  and  counting  the  fragments,  taking  a 
standard  length.  The  initial  dose  is  5  million  frag- 
ments, and  the  dose  should  be  increased  steadily 
until  cure  is  attained.  Vaccines  of  the  secondary 
infections,  if  present,  should  be  used  at  the  same 
time. 

Leprosy. — Some  successful  cases  of  this  disease 
treated  with  vaccines  of  Kedrowski's  bacillus  have 
been  recorded.  I  have  obtained  focal  and  general 
reactions  in  ten  or  more  cases,  with  a  vaccine  of  a 
non-acid-fast  diphtheroid  bacillus  isolated  from 
lepra  modules ;  but  the  results  so  far  are  not 
sufficiently  good  to  warrant  further  description  at 
present. 


220 


INDEX. 


Acidosis,  40,  152 
Acne,  166,  167 
Actinomycosis,  219 
Adenoids,  114 
Agglutinins,  42 
Agglutinoids,  43 
Aggressins,  46 
Alexin,  30 
Amboceptor,  30 
Anaphylaxis,  47 
Andrews,  27 

Anterior  poliomyelitis,  196 
Anthrax,  164,  165 
Antiformin,  211 
Antistaphylococcic  serum,  36 
Antistreptococcic  serum,  36 
Antitoxic  sera,  20 
Antitoxins,  19,  20,  65 
Antitrypsin,  11,  19 
Appendicitis,  97 
Arrhenius  and  Madsen,  25 
Arteriosclerosis,  178 
Arthritis,  147,  152 
Asthma,  115 

B.  aerobicus  sepis,  159 

B.  cholercB,  29,  76,  77 

B.  coli,  7,  85,  98,  102,  III,  123, 

130,  132,  141,  159 
B.  diphtheric^,  23,  104 
B.  enteritidis,  78 
B.  fusiformis,  81,  82,  116 
B,  influenzcs,  iii 
B.  Melitensis,  174,  175 
B.  perfringens,  158 
B.  pertussis,  111,  114 
B.  pestis,  9,  183 
B.  proteus,  171 

B.  pyocyaneus,  78,98, 1 11, 159, 
205 

B.  suhtilis,  191 

B.  xerosis,  201,  203 


Bacillus  of  malignant  oedema, 
158 

Bactericidal  substances,  34,  65 
Bacteriolysis,  29,  65 
Bacteriotropin,  37 
Bail,  46 
Ballance,  192 
Beattie,  150 
Bile  ducts,  95 
Blitz,  26 

Blood  vessels,  178 
Bordet,  26,  30,  32 
Bright's  disease,  125 

Calmette's  conjunctival  re- 
action, 51 
Chantemesse,  18 
Chloramine  T,  143,  149 
Cholera,  29,  76,  77 
Cimex  lectularius,  181 
Coferment,  33 
Colitis,  mucous,  10 1 
Colon,  99 
Comedones,  166 
Complement,  26,  30,  32,  34 
Complementoid,  32 
Compound  fractures,  157 
Conjunctiva,  199 
Connor,  185 
Cornea,  199 
Cruickshank,  186 
Cystitis,  132 

Diabetes,  40 

Di-iodosalicylic  acid,  122,  143, 

149,  152,  161 
Diphtheria,  23,  103,  104,  105 
Diphtheroid  bacilH,  112,  185, 

205 

Diplococcus  intracellularis,  i8y 
Diplococcus  mucosus,  no 


22X 


Index. 


Diplococcus  pharyngis  siccus, 
no 

Diplococcus  rheumaticus,  1 50 
Disseminated  sclerosis,  197 
Douglas,  35,  41,  141 
Duodenum,  88 
Dysentery,  78,  80 

Ecthyma,  170 
Eczema,  170,  198,  206 
Emery,  195 

Empyema  of  pleura,  123 
Endocarditis,  177 
Endometritis,  140 
Epididymis,  135 
Erysipelas,  163 
Eusol,  143,  149 
Eustachian  tube,  204 
Eyelids,  198 

Fallopian  tubes,  145 
Ferment,  32 
Fibrositis,  157 
Fischer,  14 
Flexner,  197 
French,  151 
Furunculosis,  168,  206 

GALL-bladder,  95 
Gallstones,  96 
Gastric  ulcer,  87 
Gastritis,  84 
(^-Glucose,  13 
/-Glucose,  13 

Gonococcus,  130,  132,  135,  200 
vaccine,  138 

Gonorrhoea, 

in  male,  134 

in  female,  139 
Gout,  40,  152 

HiEMOLYSis,  30 
Haffkine's  cholera  vaccine,  9, 
77 

Haffkine's  plague  propnylac- 

tic,  9,  184 
Hay  fever,  115 

Immune-body,  21,  30,  31 


Immunity, 

acquired,  8 

active  and  passive,  8,  54 

definition  of,  i 

mixed,  10,  23 

natural,  7 
Impetigo,  170 
Intra-ocular  infections,  202 
Invertase,  14 
Iridocyclitis,  203 


Jaundice,  95 


Kedrowski,  220 
Koch-Weeks  bacillus,  200 
Kraus'  phenomenon,  44 


Labyrinth,  204 
Leishman,  35 
Leprosy,  220 
Liver,  93,  94 
Lungs,  117 
Lustig,  183 
Lymphadenoma,  185 
Lymphatic  glands,  181 


Marginal  blepharitis,  198 
Mastoid,  204 
Mediterranean  fever,  173 
Meningitis,  186 
Meningococcus,  187,  189 
Metchnikoff,  18,  27,  34 
Microbes,  virulence  of,  5,  6 
Micrococcus    catarrhalis,  81, 

109,  116,  141,  188 
Micrococcus  fiavus,  no,  188 
Micrococcus  paraietragenus, 

no 

Micrococcus  tetragenus,  no 
Middle  ear,  204 
Milk-souring  microbes,  3 
Morax-Axenfeld  bacillus,  200 
Morgan's  No.  i  bacillus,  78 
Moro,  52 

Mucous  colitis,  10 1 
Muir,  33 
Myocarditis,  176 


222 


Index. 


Nasal  catarrh,  io6 
Negative  phase,  lo,  21 
Negri,  194 
Nephritis,  125,  126 
Neufeld,  37 
Neuritis,  190 
Nitrifying  microbes,  2 
Noguchi,  196,  197 


Opotherapy,  70 
Opsonic  index,  36,  59 
Opsonins,  25,  35,  64 
Osteomyelitis,  146 
Ovaries,  145 

Ozaena  bacillus,  112,  205 


Pancreas,  89 
Parasitic  microbes,  3 
Paratyphoid,  72,  73,  75,  124, 

130,  132 
Pasteur,  165,  195 
Pavlow,  16 
Pemphigus,  170 
Pericarditis,  175 
Pfeiffer,  29,  77 
Phagocjrtosis,  34 
von  Pirquet,  52 
Plague,  181 
Pleurisy,  122 

Pneumobacillus  of  Friedlander, 

81,  no,  117,  205 
Pneumococcus,  98,  108,  116, 

117,  120 — 123,  200,  205 
Pneumonia,  117,  122 
Positive  phase,  21 
Poynton  and  Payne,  150 
Precipitins,  44 
Prototoxoid,  24 
Pyorrhoea  alveolaris,  81 


Saprophytic  microbes,  2 
Schizomycetes,  2 
Sclavo,  165 
Seborrhoea,  166 
Sera,  antitoxic,  20 
Shennan,  141 

Side-chain  theory,  15,  16,  19 
Spleno-meduUary  leucaemia,  39 
Staphylococcus,  82,  98,  102, 
108,  116,  130,  132,  141,  146, 
159,  167 — 171,  197,  198,  200, 
205 
Starling,  99 

Streptococcus,  85,  98,  102,  109, 
116,  130,  132,  141,  146,  159, 
163,  170,  171,  175,  205 

Stye,  199 

Substance  sensibilisatrice,  30 
Sycosis,  168 
Symbiotic  microbes,  3 
Szendeffy,  62 


Testis,  135,  144 
Tetanolysin,  15 
Tetanospasmin,  12,  14,  15 
Tetanus,  190 — 192 
Tonsillitis,  116 
Toxins,  4,  12 

endotoxins,  17 

exotoxins,  12 

haptophore  group  of,  15 

taxophore  (  =  zymophore) 
group  of,  15,  19 
Toxoids  (=  zymoids),  16,  23 
Toxon,  24 

Tuberculins,  214  et  seq. 
Tuberculosis,  207,  209 
Typhoid, 

antiserum,  76 
bacillus,  73,  98,  123,  130, 

132 
fever,  72 
toxin,  18,  23 
vaccine,  74 


Rabies,  193 

Reactions,  21,  58,  59,  61 
Receptors,  16 
Rheumatism,  40,  149 
Rheumatoid  arthritis,  152 
Richet,  47 
Roland,  183 

223 


Undulant  fever,  173 
Urethritis,  134 
Urine,  reaction  of,  133 


Index. 


Vaccines,  54,  68,  69 


Weichselbaum,  187 
Whooping-cough,  114 
Widal  reaction,  43 
Wounds,  157 

Wright  and  Douglas,  35,  41 


Xenopsyll  us(^  —  Pulex  cheopis) , 
181 

Yersin,  183 

Zones  of  inhibition,  43 


THE  WHITEFRIARS  PRESS,  LTD.,  LONDON  AND  TONBRIDGK. 


